4-amino-1,3-thiazine or oxazine derivative

ABSTRACT

The present invention provide a medicament for treating the diseases induced by production, secretion or deposition of amyloid-β proteins, for example, a compound of the following formula (I) wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, ring A, Y and the dotted line are defined in the specification, its pharmaceutically acceptable salt or a solvate thereof.

TECHNICAL FIELD

The present invention relates to a compound which has amyloid βproduction inhibitory activity, and is useful as an agent for treatingor preventing disease induced by production, secretion and/or depositionof amyloid β protein.

BACKGROUND ART

In the brain of Alzheimer's patient, the peptide composed of about 40amino acids residue as is called amyloid β protein, that accumulates toform insoluble specks (senile specks) outside nerve cells is widelyobserved. It is concerned that this senile specks kill nerve cells tocause Alzheimer's disease, so the therapeutic agents for Alzheimer'sdisease, such as decomposition agents of amyloid β protein and amyloidvaccine, are under investigation.

Secretase is an enzyme which cleaves a protein called amyloid 3precursor protein (APP) in cell and produces amyloid β protein. Theenzyme which controls the production of N terminus of amyloid β proteinis called as β-secretase (beta-site APP-cleaving enzyme 1, BACE1). It isthought that inhibition of this enzyme leads to reduction of producingamyloid β protein and that the therapeutic agent for Alzheimer's diseasewill be created due to the inhibition.

Patent Literatures 1 to 11 and Non-patent Literatures 5 and 6 describethe compounds which are structurally similar to the compounds of thepresent invention, and the compounds can be the therapeutic agent forAlzheimer's disease or Alzheimer's disease-related symptom. However, allcompounds substantively disclosed in these literatures have differentcore structures from the present invention. Patent Literature 12describes the compounds which are structurally similar to the compoundsof the present invention, however, the effect for Alzheimer's disease isnot suggested. Non-patent Literatures 1 to 4 describe the compoundswhich are structurally similar to the compounds of the presentinvention, however, there is no suggestion that these compounds have amedical use.

PRIOR ART LITERATURES Patent Literatures

-   [Patent Literature 1] International Patent Application Publication    WO2007/058583-   [Patent Literature 2] International Patent Application Publication    WO2007/049532-   [Patent Literature 3] International Patent Application Publication    WO2008/133273-   [Patent Literature 4] International Patent Application Publication    WO2008/133274-   [Patent Literature 5] International Patent Application Publication    WO2009/103626-   [Patent Literature 6] International Patent Application Publication    WO2009/134617-   [Patent Literature 7] International Patent Application Publication    WO2010/019392-   [Patent Literature 8] International Patent Application Publication    WO2010/019393-   [Patent Literature 9] International Patent Application Publication    WO2009/151098-   [Patent Literature 10] International Patent Application Publication    WO2010/047372-   [Patent Literature 11] US Patent Application Publication US    2010/0261727-   [Patent Literature 12] U.S. Pat. No. 5,328,915

Non-Patent Literatures

-   [Non-Patent Literature 1] Chemistry of Heterocyclic Compounds    (2001), 37 (4), 522-523-   [Non-Patent Literature 2] Russian Journal of Organic Chemistry    (2000), 36 (12), 1739-1742-   [Non-Patent Literature 3] Russian Journal of Organic Chemistry    (1997), 33 (1), 96-102-   [Non-Patent Literature 4] Journal of Organic Chemistry (1983), 48    (4), 623-625-   [Non-Patent Literature 5] Bioorganic & Medicinal Chemistry Letters    (2010), 20 (3), 1269-1271-   [Non-Patent Literature 6] Bioorganic & Medicinal Chemistry Letters    (2010), 20 (7), 2279-2282

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

The present invention provides compounds which have reducing effects toproduce amyloid β protein, especially β secretase inhibitory activity,and are useful as an agent for treating or preventing disease induced byproduction, secretion and/or deposition of amyloid β protein.

Means to Solve the Problems

The present invention, for example, provides the inventions described inthe following items.

(1) A compound of formula (I):

wherein

—X— is —O—, —S—, —SO—, —SO₂— or —N(R^(x))—,

R^(x) is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, ring A is a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle,—Y— is substituted or unsubstituted alkenylene, substituted orunsubstituted alkynylene, —(CR⁵R⁶)_(n)—, —(CR⁵R⁶)_(n)O(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)S(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)SO₂(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)SO(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)N(R⁷)(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)N(R⁷)(CR⁵R⁶)_(m)—, or—(CR⁵R⁶)_(n)N(R⁷)C(═O)(CR⁵R⁶)_(m)—,R⁵ and R⁶ are each independently, hydrogen, halogen, hydroxy, nitro,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted carbamoyloxy, substituted orunsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl,substituted or unsubstituted aminosulfinyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl,R⁷ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,n and m are each independently an integer of 0 to 3,R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,R^(3a), R^(3b), R^(4a) and R^(4b) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl,R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(3a) and R^(4a) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,dashed line means the presence or absence of a bond,when dashed line means the presence of a bond, then R^(3b) and R^(4b)are absent,provided that when —X— is —O— or —N(R^(x))—, and R^(3a) and R^(4a)together with the carbon atom to which they are attached form asubstituted or unsubstituted benzene ring, then ring A is not (i) phenylsubstituted only with halogen or (ii) phenyl substituted withsubstituted or unsubstituted phenyl at m-position,its pharmaceutically acceptable salt or a solvate thereof.(1′) A compound of formula (I):

wherein

—X— is —O—, —S—, —SO—, —SO₂— or —N(R^(x))—,

R^(x) is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclyloxycarbonyl, substituted orunsubstituted carbocyclylsulfinyl, substituted or unsubstitutedcarbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl,ring A is a substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle,—Y— is substituted or unsubstituted alkenylene, substituted orunsubstituted alkynylene, —(CR⁵R⁶)_(n)—, —(CR⁵R⁶)_(n)O(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)S(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)SO₂(CR⁵R⁶)_(m),—(CR⁵R⁶)_(n)SO(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)N(R⁷)(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)N(R⁷)(CR⁵R⁶)_(m)—, or—(CR⁵R⁶)_(n)N(R⁷)C(═O)(CR⁵R⁶)_(m)—,R⁵ and R⁶ are each independently, hydrogen, halogen, hydroxy, nitro,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted carbamoyloxy, substituted orunsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl,substituted or unsubstituted aminosulfinyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclyloxycarbonyl, substituted orunsubstituted carbocyclylsulfinyl, substituted or unsubstitutedcarbocyclylsulfonyl, a substituted or unsubstituted heterocyclic group,substituted or unsubstituted heterocyclyloxy, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclylsulfinyl orsubstituted or unsubstituted heterocyclylsulfonyl,R⁷ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,n and m are each independently an integer of 0 to 3,R¹ is substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,R^(3a), R^(3b), R^(4a) and R^(4b) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl,R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,R^(3a) and R^(4a) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle,dashed line means the presence or absence of a bond,when dashed line means the presence of a bond, then R^(3b) and R^(4b)are absent,provided that when X— is —O— or —N(R^(x))—, and R^(3a) and R^(4a)together with the carbon atom to which they are attached form asubstituted or unsubstituted benzene ring, then ring A is not (i) phenylsubstituted only with halogen or (ii) phenyl substituted withsubstituted or unsubstituted phenyl at m-position,its pharmaceutically acceptable salt or a solvate thereof.(2) The compound according to the item (1) or (1′) wherein Y is—(CR⁵R⁶)_(n)— and n is 0, its pharmaceutically acceptable salt or asolvate thereof.(3) The compound according to the item (2) wherein —X— is —O— or —S—,its pharmaceutically acceptable salt or a solvate thereof.(4) The compound according to any one of the items (1), (1′), (2) and(3) wherein ring A is a group of formula:

wherein ring A′ and ring B are each independently a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,—Z— is -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or -L¹-N(R⁸)-L²-,L¹ and L² are each independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted alkenylene or substituted orunsubstituted alkynylene,R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,provided that —Z— is -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or-L¹-N(R⁸)-L²-, then L¹ bonds to the ring B, and, L² bonds to the ringA′,its pharmaceutically acceptable salt or a solvate thereof.(5) The compound according to the item (4) wherein —Z— is —C(═O)N(R⁸)—,its pharmaceutically acceptable salt or a solvate thereof.(6) The compound according to the item (4) or (5) wherein ring A′ issubstituted or unsubstituted benzene, its pharmaceutically acceptablesalt or a solvate thereof.(7) The compound according to any one of the items (4) to (6) whereinring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazine, itspharmaceutically acceptable salt or a solvate thereof.(8) The compound according to any one of the items (1), (1′) and (2) to(7) wherein R^(3a), R^(3b), R^(4a) and R^(4b) are all hydrogen, itspharmaceutically acceptable salt or a solvate thereof.(9) The compound according to any one of the items (1), (1′) and (2) to(7) wherein R^(3a) and R^(4a) together with the carbon atom to whichthey are attached form a substituted or unsubstituted benzene ring, itspharmaceutically acceptable salt or a solvate thereof.(10) The compound according to any one of the items (1), (1′) and (2) to(9) wherein R¹ is C1 to C3 unsubstituted alkyl, its pharmaceuticallyacceptable salt or a solvate thereof.(11) The compound according to any one of the items (1), (1′) and (2) to(10) wherein R^(2a) and R^(2b) are both hydrogen, its pharmaceuticallyacceptable salt or a solvate thereof.(12) A pharmaceutical composition comprising the compound according toany one of the items (1), (1′) and (2) to (11), its pharmaceuticallyacceptable salt or a solvate thereof as an active ingredient.(13) A pharmaceutical composition having BACE1 inhibitory activitycomprising the compound according to any one of the items (1), (1′) and(2) to (11), its pharmaceutically acceptable salt or a solvate thereofas an active ingredient.(14) The pharmaceutical composition according to the item (12) or (13),which is a medicament for treating or preventing the diseases induced byproduction, secretion or deposition of amyloid-β proteins.(15) The pharmaceutical composition according to the items (12) or (13),which is a medicament for treating or preventing Alzheimer's disease.(16) A method for inhibiting BACE1 activity comprising administering thecompound according to any one of the items (1), (1′) and (2) to (11),its pharmaceutically acceptable salt or a solvate thereof.(17) The compound according to any one of items (1), (1′) and (2) to(11), its pharmaceutically acceptable salt or a solvate thereof for usein a method for inhibiting BACE1 activity.(18) A method for treating or preventing diseases induced by production,secretion or deposition of amyloid-β proteins comprising administeringthe compound according to any one of items (1) to (11), itspharmaceutically acceptable salt or a solvate thereof.(19) The compound according to any one of the items (1), (1′) and (2) to(11), its pharmaceutically acceptable salt or a solvate thereof for usein a method for treating or preventing diseases induced by production,secretion or deposition of amyloid-β proteins.(20) A method for treating or preventing Alzheimer's disease comprisingadministering the compound according to any one of the items (1), (1′)and (2) to (11), its pharmaceutically acceptable salt or a solvatethereof.(21) The compound according to any one of the items (1), (1′) and (2) to(11), its pharmaceutically acceptable salt or a solvate thereof fortreating or preventing Alzheimer's disease.(22) Use of the compound according to any one of the items (1), (1′) and(2) to (11), or its pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for inhibiting β secretaseactivity,(23) Use of the compound according to any one of the items (1), (1′) and(2) to (11), or its pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for treating or preventingdisease induced by production, secretion or deposition of amyloid βprotein,(24) Use of the compound according to any one of the items (1), (1′) and(2) to (11), or its pharmaceutically acceptable salt or a solvatethereof in the manufacture of a medicament for treating or preventingAlzheimer's disease.(25) A method, a system, an apparatus, a kit or the like for preparingthe compound according to any one of the item (1), (1′) and (2) to (11),or its pharmaceutically acceptable salt or a solvate thereof.(26) A method, a system, an apparatus, a kit or the like for preparingthe pharmaceutical composition comprising the compound according to anyone of the item (1), (1′) and (2) to (11), or its pharmaceuticallyacceptable salt or a solvate thereof.(27) A method, a system, an apparatus, a kit or the like for using thecompound according to any one of the item (1), (1′) and (2) to (11), orits pharmaceutically acceptable salt or a solvate thereof.

Effect of the Invention

The compounds of the present invention are useful as an agent fortreating or preventing disease induced by production, secretion ordeposition of amyloid β protein such as Alzheimer's disease and thelike.

BEST MODE FOR CARRYING OUT THE INVENTION

As used herein, the “halogen” includes fluorine, chlorine, bromine, andiodine.

As used herein, the “alkyl” includes straight or branched alkyl of acarbon number of 1 to 15, for example, a carbon number of 1 to 10, forexample, a carbon number of 1 to 6, and for example, a carbon number of1 to 3. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl,isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.

In the specification, an alkyl part of the “alkoxy”, the“halogenoalkyl”, the “hydroxyalkyl”, the “halogenoalkoxy”, the“alkylcarbonyl”, the “hydroxyalkoxy”, “alkoxycarbonyl”, the“halogenoalkoxycarbonyl”, the “alkylamino”, the “aminoalkyl”, the“alkoxyalkoxy”, the “alkoxyalkenyloxy”, the “alkoxyalkynyl”, the“alkylcarbamoyl”, the “hydroxyalkylcarbamoyl”, the “alkoxyimino”, the“alkylthio”, the “alkylsulfonyl”, the “alkylsulfonylamino”, the“alkylsulfonylalkylamino”, the “alkylsulfonylimino”, the“alkylsulfinylamino”, the “alkylsulfinylalkylamino”, the“alkylsulfinylimino”, the “alkylsulfamoyl”, the “alkylsulfinyl”, the“carbocyclylalkyl”, the “carbocyclylalkoxy”, the“carbocyclylalkoxycarbonyl”, the “carbocyclylalkylamino”, the“carbocyclylalkylcarbamoyl”, the “cycloalkylalkyl”, the“cycloalkylalkoxy”, the “cycloalkylalkylamino”, the“cycloalkylalkoxycarbonyl”, the “cycloalkylalkylcarbamoyl”, the“arylalkyl”, the “arylalkoxy”, the “arylalkylamino”, the“arylalkoxycarbonyl”, the “arylalkylcarbamoyl”, the “heterocyclylalkyl”,the “heterocyclylalkoxy”, the “heterocyclylalkylamino”, the“heterocyclylalkoxycarbonyl” and “heterocyclylalkylcarbamoyl” is thesame as the above alkyl.

In the specification, the “substituted or un substituted alkyl” may besubstituted with one or more substituents selected from a substituentgroup α.

As used herein, the substituent group α is a group consisting ofhalogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy,acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino,imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl,hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl,alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino,alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano,nitro, a carbocyclic group and a heterocyclic group wherein thecarbocycle and the heterocycle may be each substituted with one or moresubstituents selected from a group consisting of halogen, alkyl, hydroxyand alkoxy.

In the specification, examples of the substituent of the “substituted orun substituted alkoxy”, the “substituted or un substitutedalkoxycarbonyl”, the “substituted or un substituted alkylthio”, the“substituted or un substituted alkylsulfonyl” and the “substituted or unsubstituted alkylsulfinyl” include one or more groups selected from theabove substituent group α.

In the specification, examples of an embodiment of the “halogenoalkyl”include trifluoromethyl, fluoromethyl and trichloromethyl.

In the specification, examples of an embodiment of the “halogenoalkoxy”include trifluoromethoxy, fluoromethoxy and trichloromethoxy.

In the specification, the “alkylidene” includes a divalent group of theabove “alkyl”, and examples include methylidene, ethylidene,propylidene, isopropylidene, butylidene, pentylidene and hexylidene.

In the specification, the “alkenyl” includes straight or branchedalkenyl of a carbon number of 2 to 15, for example, a carbon number of 2to 10, for example, a carbon number of 2 to 6 for example, a carbonnumber of 2 to 4, having one or more double bonds at any availableposition. Examples include vinyl, allyl, propenyl, isopropenyl, butenyl,isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl,hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tridecenyl, tetradecenyl and pentadecenyl.

In the specification, an alkenyl part of the “alkenyloxy”, the“alkenyloxycarbonyl”, the “alkenylcarbonyl”, the “alkoxyalkenyloxy”, the“alkenylthio”, the “alkenylamino”, the “alkenylsulfonyl” and the“alkenylsulfinyl” is the same as the above “alkenyl”.

In the specification, the “alkynyl” includes straight or branchedalkynyl of a carbon number of 2 to 10, for example, a carbon number of 2to 8, for example, a carbon number of 3 to 6, having one or more triplebonds at any available position. Examples include ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl.These may further a double bond at any available position.

In the specification, an alkynyl part of the “alkoxyalkynyl”, the“alkynyloxy”, the “alkynyloxycarbonyl”, the “alkoxyalkynyloxy”, the“alkynylthio”, the “alkynylsulfinyl”, the “alkynylsulfonyl” and the“alkynylamino” is the same as the above “alkynyl”.

In the specification, examples of the substituent of the “substituted orunsubstituted alkenyl”, the “substituted or unsubstituted alkenyloxy”,the “substituted or unsubstituted alkenyloxycarbony”, the “substitutedor unsubstituted alkenylthio”, the “substituted or unsubstitutedalkenylsulfinyl”, the “substituted or unsubstituted alkenylsulfonyl”,the “substituted or unsubstituted alkynyl”, the “substituted orunsubstituted alkynyloxy”, the “substituted or unsubstitutedalkynylthio”, the “substituted or unsubstituted alkynyloxycarbony”, the“substituted or unsubstituted alkynylsulfinyl” and the “substituted orunsubstituted alkynylsulfonyl” include one or more substituents selectedfrom the above substituent group α.

In the specification, examples of the substituents of the “substitutedor unsubstituted amino”, the “substituted or unsubstitutedaminosulfinyl”, the “substituted or unsubstituted carbamoyl”, the“substituted or unsubstituted carbamoyloxy”, the “substituted orunsubstituted thiocarbamoyl” and the “substituted or unsubstitutedsulfamoyl” include 1 to 2 substituents selected from alkyl, acyl,hydroxy, alkoxy, alkoxycarbonyl, a carbocyclic group and a heterocyclicgroup.

In the specification, the “acyl” includes formyl, alkylcarbonyl of acarbon number of 1 to 10, alkenylcarbonyl of a carbon number of 2 to 10,alkynylcarbonyl of a carbon number of 2 to 20, carbocyclylcarbonyl andheterocyclylcarbonyl. Examples include formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl,methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl,furancarbonyl, thiophenecarbonyl, benzothiazolecarbonyl,pyrazinecarbonyl, piperidinecarbonyl, and thiomorpholino.

In the specification, an acyl part of the “acyloxy” and the “acylamino”is the same as the above “acyl”.

In the specification, examples of the substituent of the “substituted orunsubstituted acyl” and “substituted or unsubstituted acyloxy” includeone or more substituents selected from the substituent group α. Inaddition, a ring part of the carbocyclylcarbonyl and theheterocyclylcarbonyl may be substituted with one or more substituentsselected from alkyl, a substituent group α, and alkyl substituted withone or more groups selected from the substituent group α.

In the specification, the “carbocyclic group” includes cycloalkyl,cycloalkenyl, aryl and a non-aromatic fused carbocyclic group.

In the specification, the “cycloalkyl” is a carbocyclic group of acarbon number of 3 to 10, for example, a carbon number of 3 to 8, andfor example, a carbon number of 4 to 8. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyland cyclodecyl.

In the specification, a cycloalkyl part of the “cycloalkylalkyl”, the“cycloalkyloxy”, the “cycloalkylalkoxy”, the “cycloalkylthio”, the“cycloalkylamino”, the “cycloalkylalkylamino”, the“cycloalkylsulfamoyl”, the “cycloalkylsulfonyl”, the“cycloalkylcarbamoyl”, the “cycloalkylalkylcarbamoyl”, the“cycloalkylalkoxycarbonyl”, and the “cycloalkyloxycarbonyl” is the sameas the above “cycloalkyl”.

In the specification, the “cycloalkenyl” includes the cycloalkyl havingone or more double bonds at any available position in the ring, andexamples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptynyl, cyclooctynyl and cyclohexadienyl.

In the specification, the “aryl” includes phenyl, naphthyl, anthryl andphenanthryl, and specific example is phenyl.

In the specification, the “non-aromatic fused carbocyclic group”includes a non-aromatic group in which two or more cyclic groupsselected from the above “cycloalkyl”, the above “cycloalkenyl” and theabove “aryl” are fused, and examples include indanyl, indenyl,tetrahydronaphthyl and fluorenyl.

In the specification, a carbocyclyl part of the “carbocycle”, the“carbocyclyloxy”, the “carbocyclylalkyl”, the “carbocyclylalkoxy”, the“carbocyclylalkoxycarbonyl”, the “carbocyclylthio”, the“carbocyclylamino”, the “carbocyclylalkylamino”, the“carbocyclylcarbonyl”, the “carbocyclylsulfamoyl”, the“carbocyclylsulfonyl”, the “carbocyclylcarbamoyl”, the“carbocyclylalkylcarbamoyl”, the “carbocyclyloxycarbonyl”, the“carbocyclylsulfinyl” and the “carbocyclylsulfonyl” is the same as the“carbocyclic group”.

In the specification, an aryl part of the “arylalkyl”, the “aryloxy”,the “aryloxycarbonyl”, the “arylalkoxycarbonyl”, the “arylthio”, the“arylamino”, the “arylalkoxy”, the “arylalkylamino”, the “arylsulfonyl”,the “arylsulfamoyl”, the “arylcarbamoyl” and the “arylalkylcarbamoyl” isthe same as the “aryl”.

In the specification, the “heterocyclic group” includes a heterocyclicgroup having one or more hetero atoms optionally selected from O, S andN in a ring, and examples include 5- to 6-membered heteroaryl such aspyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl,oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl and thiadiazolyl;

non-aromatic heterocyclic groups such as dioxanyl, thiiranyl, oxyranyl,oxetanyl, oxathioranyl, azetidinyl, thianyl, thiazolidinyl,pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino,thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl,tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl,tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl,hexahydroazepinyl, tetrahydrodiazepinyl and tetrahydropyridazinyl;fused bicyclic heterocyclic groups such as indolyl, isoindolyl,indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl,purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl,benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl,benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl,benzothienyl, benzotriazolyl, thienopyridyl, thienopyrrolyl,thienopyrazolyl, thienopyrazinyl, furopyrrolyl, thienothienyl,imidazopyridyl, imidazopyrazolyl, pyrazolopyridyl, pyrazolopyrazinyl,thiazolopyridyl, pyrazolopyrimidinyl, pyrazolotrianidyl,pyridazolopyridyl, triazolopyridyl, imidazothiazolyl,pyrazinopyridazinyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, dihydrobenzofuryl, dihydrobenzoxazinyl,dihydrobenzimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuryl,benzodioxolyl, benzodioxonyl, chromanyl, chromenyl, octahydrochromenyl,dihydrobenzodioxinyl, dihydrobenzoxezinyl, dihydrobenzodioxepinyl anddihydrothienodioxinyl;fused tricyclic heterocyclic groups such as carbazolyl, acridinyl,xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl,imidazoquinolyl and tetrahydrocarbazolyl. Examples include a 5- to6-membered heteroaryl or a non-aromatic heterocyclic group.

In the specification, a heterocyclyl part of the “heterocycle”, the“heterocyclylalkyl”, the “heterocyclyloxy”, the “heterocyclylthio”, the“heterocyclycarbonyl”, the “heterocyclylalkoxy”, the“heterocyclylamino”, the “heterocyclylsulfamoyl”, the“heterocyclylsulfonyl”, the “heterocyclylcarbamoyl”, the“heterocyclyloxycarbonyl”, the “heterocyclylalkylamino”, the“heterocyclylalkoxycarbonyl”, the “heterocyclylalkylcarbamoyl” and the“heterocyclylsulfinyl” is the same as the “heterocyclic group”.

A bond of the above “heterocyclic group” may be situated on any ring.

In the specification, the “heteroaryl” includes an aromatic cyclic groupamong the “heterocyclic group”.

In the specification, preferred examples of the ring A includes thegroups as follows:

wherein the ring A′ and ring B are each independently substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,L¹, L² and L³ are each independently a bond, substituted orunsubstituted alkylene, substituted or unsubstituted alkenylene orsubstituted or unsubstituted alkynylene,

═W¹ is ═O, ═S or ═NR⁹, W² is O, S or N(R⁸),

R⁸ is hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orunsubstituted acyl,R⁹ is hydrogen, hydroxy, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl,when the ring A is (i), then a carbon atom constituting L¹ and a carbonatom constituting L² or an N atom of W² and a carbon atom constitutingL² may bind each other via substituted or unsubstituted alkylene to forma ring,when the ring A is (ii), then a carbon atom constituting L¹ and a carbonatom constituting L² or a carbon atom constituting L¹ and an N atom ofW² may bind each other via substituted or unsubstituted alkylene to forma ring,when the ring A is (iii), then two N atoms of W² may bind each other viasubstituted or unsubstituted alkylene to form a ring,when the ring A is (vi), then a carbon atom constituting L¹ and a carbonatom constituting L² may bind each other via substituted orunsubstituted alkylene to form a ring,p is 1 or 2, andwhen there are two or more L³s, W²s, or R⁹s in the above formula, theymay be each independently different from each other.

Further preferred examples of the ring A includes the groups as follows:

wherein L is each independently a bond, substituted or unsubstitutedalkylene, substituted or unsubstituted alkenylene or substituted orunsubstituted alkynylene,ring T is a carbocycle which may be substituted with the substituent(s)selected from the substituent group α or a heterocycle which may besubstituted with the substituent(s) selected from the substituent groupα, and other symbols are as defined above.

More specific examples of the ring A includes the groups as follows:

wherein symbols are as defined above.

wherein symbols are as defined above.

As another embodiment of the present invention, examples of thesubstituent of the “substituted or unsubstituted carbocycle”, the“substituted or unsubstituted heterocycle”, the “substituted orunsubstituted benzene”, the “substituted or unsubstituted benzene ring”,the “substituted or unsubstituted pyridine”, the “substituted orunsubstituted pyrimidine” and the “substituted or unsubstitutedpyrazine” of the ring A, the ring A′ and the ring B include: asubstituent selected from the substituent group α, for example, halogen,hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl,amino, cyano, alkylamino and/or alkylthio etc.; alkyl substituted withone or more substituents selected from the substituent group α,hydroxyimino and alkoxyimino, herein, the substituent is, for example,halogen, hydroxy, alkoxy and/or alkoxycarbonyl etc. or unsubstitutedalkyl;

aminoalkyl substituted with one or more substituents selected from thesubstituent group α; herein, the substituent is, for example, acyl,alkyl and/or alkoxy etc.;alkenyl substituted with one or more substituents selected from thesubstituent group α, herein, the substituent is, for example,alkoxycarbonyl, halogen and/or halogenoalkoxycarbonyl etc. orunsubstituted alkenyl;alkynyl substituted with one or more substituents selected from thesubstituent group α, herein, the substituent is, for example,alkoxycarbonyl etc. or unsubstituted alkynyl;alkoxy substituted with one or more substituents selected from thesubstituent group α, herein, the substituent is, for example, halogen,carbamoyl, alkylcarbamoyl and/or hydroxyalkylcarbamoyl etc.;alkoxyalkoxy substituted with one or more substituents selected from thesubstituent group α;alkenyloxy substituted with one or more substituents selected from thesubstituent group α, herein, the substituent is, for example, halogen,hydroxy, amino and/or alkylamino etc. or unsubstituted alkenyloxy;alkoxyalkenyloxy substituted with one or more substituents selected fromthe substituent group α;alkynyloxy substituted with one or more substituents selected from thesubstituent group α, herein, the substituent is, for example, halogenand/or hydroxy etc. or unsubstituted alkynyloxy, alkoxyalkynyloxysubstituted with one or more groups selected from the substituent groupα;alkylthio substituted with one or more substituents selected from thesubstituent group α or unsubstituted alkylthio;alkenylthio substituted with one or more substituents selected from thesubstituent group α or unsubstituted alkenylthio;alkynylthio substituted with one or more substituents selected from thesubstituent group α or unsubstituted alkynylthio;alkylamino substituted with one or more substituents selected from thesubstituent group α;alkenylamino substituted with one or more substituents selected from thesubstituent group α;alkynylamino substituted with one or more substituents selected from thesubstituent group α;aminooxy substituted with one or more substituents selected from thesubstituent group α and alkylidene, or unsubstituted aminooxy;acyl substituted with one or more substituents selected from thesubstituent group α;alkylsulfonyl substituted with one or more substituents selected fromthe substituent group α or unsubstituted alkylsulfonyl;alkylsulfinyl substituted with one or more substituents selected fromthe substituent group α or unsubstituted alkylsulfinyl;alkylsulfamoyl substituted with one or more substituents selected fromthe substituent group α;a carbocyclic group, e.g. cycloalkyl, aryl and the like, substitutedwith one or more substituents selected from the substituent group α,azide, alkyl and halogenoalkyl;a heterocyclic group substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl;carbocyclylalkyl, e.g. cycloalkylalkyl, arylalkyl and the like,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylalkyl;heterocyclylalkyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylalkyl;carbocyclyloxy, e.g. cycloalkoxy, aryloxy and the like, substituted withone or more substituents selected from the substituent group α, azide,alkyl and halogenoalkyl, or unsubstituted carbocyclyloxy, e.g.cycloalkylalkyl, arylalkyl and the like;heterocyclyloxy substituted with one or more substituents selected fromthe substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclyloxy;carbocyclylalkoxy, e.g. cycloalkylalkoxy, arylalkoxy and the like,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylalkoxy, e.g. cycloalkylalkoxy, arylalkoxy and the like;heterocyclylalkoxy substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylalkoxy;carbocyclylalkoxycarbonyl, e.g. cycloalkylalkoxycarbonyl,arylalkoxycarbonyl and the like, substituted with one or moresubstituents selected from the substituent group α, azide, alkyl andhalogenoalkyl, or unsubstituted carbocyclylalkoxycarbonyl, e.g.cycloalkylalkoxycarbonyl, arylalkoxycarbonyl and the like;heterocyclylalkoxycarbonyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkoxycarbonyl;carbocyclylthio, e.g. cycloalkylthio, arylthio and the like, substitutedwith one or more substituents selected from the substituent group α,azide, alkyl and halogenoalkyl, or unsubstituted carbocyclylthio, e.g.cycloalkylthio, arylthio and the like;heterocyclylthio substituted with one or more substituents selected fromthe substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylthio;carbocyclylamino, e.g. cycloalkylamino, arylamino and the like,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylamino, e.g. cycloalkylamino, arylamino and the like;heterocyclylamino substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylamino;carbocyclylalkylamino, e.g. cycloalkylalkylamino, arylalkylamino and thelike, substituted with one or more substituents selected from thesubstituent group α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylalkylamino, e.g. cycloalkylalkylamino, arylalkylamino and thelike;heterocyclylalkylamino substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkylamino;carbocyclylsulfamoyl, e.g. cycloalkylsulfamoyl, arylsulfamoyl and thelike, substituted with one or more substituents selected from thesubstituent group α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylsulfamoyl;heterocyclylsulfamoyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylsulfamoyl;carbocyclylsulfonyl, e.g. cycloalkylsulfonyl, arylsulfonyl and the like,substituted with one or more substituents selected from the substituentgroup α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylsulfonyl, e.g. cycloalkylsulfonyl, arylsulfonyl and the like;heterocyclylsulfonyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylsulfonyl;carbocyclylcarbamoyl, e.g. cycloalkylcarbamoyl, arylcarbamoyl and thelike, substituted with one or more substituents selected from thesubstituent group α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclylcarbamoyl, e.g. cycloalkylcarbamoyl, arylcarbamoyl and thelike;heterocyclylcarbamoyl substituted with one or more substituents selectedfrom the substituent group α, azide, alkyl and halogenoalkyl, orunsubstituted heterocyclylcarbamoyl;carbocyclylalkylcarbamoyl, e.g. cycloalkylalkylcarbamoyl,arylalkylcarbamoyl and the like, substituted with one or moresubstituents selected from the substituent group α, azide, alkyl andhalogenoalkyl, or unsubstituted carbocyclylalkylcarbamoyl, e.g.cycloalkylalkylcarbamoyl, arylalkylcarbamoyl and the like;heterocyclylalkylcarbamoyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclylalkylcarbamoyl;carbocyclyloxycarbonyl, e.g. cycloalkyloxycarbonyl, aryloxycarbonyl andthe like, substituted with one or more substituents selected from thesubstituent group α, azide, alkyl and halogenoalkyl, or unsubstitutedcarbocyclyloxycarbonyl, e.g. cycloalkoxycarbonyl, aryloxycarbonyl andthe like;heterocyclyloxycarbonyl substituted with one or more substituentsselected from the substituent group α, azide, alkyl and halogenoalkyl,or unsubstituted heterocyclyloxycarbonyl;alkylenedioxy substituted with halogen, or unsubstituted alkylenedioxy;oxo; andazide. The aforementioned ring of ring A, ring A′ and ring B each may besubstituted with one or more substituents selected from them.

In the specification, examples of the substituent of the “substituted orunsubstituted carbocycle”, the “substituted or unsubstituted benzene”,the “substituted or unsubstituted heterocycle”, the “substituted orunsubstituted pyridine”, the “substituted or unsubstituted pyrimidine”and the “substituted or unsubstituted pyrazine” in ring A′ and ring Binclude halogen, cyano, hydroxy, nitro, carboxy, alkyl substituted withone or more substituents selected from the substituent group α,unsubstituted alkyl, alkoxy substituted with one or more substituentsselected from the substituent group α, unsubstituted alkoxy, aminosubstituted with one or more substituents selected from the substituentgroup α, unsubstituted amino, carbamoyl substituted with one or moresubstituents selected from the substituent group α, unsubstitutedcarbamoyl, alkoxycarbonyl substituted with one or more substituentsselected from the substituent group α, and unsubstituted alkoxycarbonyl.

In the specification, examples of the substituent except “—Z-ring B” ofthe “substituted or unsubstituted carbocycle” or the “substituted orunsubstituted heterocycle” in ring A include halogen, hydroxy, alkyl,alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy, acyl, carboxy,alkoxycarbonyl, amino or cyano.

In the specification, examples of the substituent of the “substituted orunsubstituted carbocycle”, the “substituted or unsubstituted benzene” orthe “substituted or unsubstituted heterocycle” in ring A′ includehalogen.

In the specification, examples of the substituent of the “substituted orunsubstituted carbocycle”, the “substituted or unsubstitutedheterocycle”, “substituted or unsubstituted pyridine”, the “substitutedor unsubstituted pyrimidine” and the “substituted or unsubstitutedpyrazine” in ring B include halogen, hydroxy, alkyl, alkenyl, alkynyl,alkoxy, alkenyloxy, alkynyloxy, acyl, carboxy, alkoxycarbonyl, amino orcyano.

In the specification, examples of the substituent of the “substituted orunsubstituted carbocyclic group”, the “substituted or unsubstitutedcarbocyclylthio”, the “substituted or unsubstituted carbocyclylalkyl”,the “substituted or unsubstituted carbocyclylalkoxy”, the “substitutedor unsubstituted carbocyclyloxycarbonyl”, the “substituted orunsubstituted carbocyclyloxy” the “substituted or unsubstitutedcarbocyclylsulfinyl”, the “substituted or unsubstitutedcarbocyclylsulfonyl”, the “substituted or unsubstituted heterocyclicgroup”, the “substituted or unsubstituted heterocyclyloxy”, the“substituted or unsubstituted heterocyclylthio”, the “substituted orunsubstituted heterocyclylalkyl”, the “substituted or unsubstitutedheterocyclylalkoxy”, “substituted or unsubstitutedheterocyclyloxycarbonyl”, the “substituted or unsubstitutedheterocyclylsulfinyl”, the “substituted or unsubstitutedheterocyclylsulfonyl” and the “substituted or unsubstituted heterocycle”in other than the above ring A, ring A′ and ring B include one or moresubstituents selected from (i) alkyl substituted with one or moresubstituents selected from the substituent group α, (ii) unsubstitutedalkyl and (iii) the substituent group α.

In the specification, the “alkylene” includes a straight or brancheddivalent carbon chain of a carbon number of 1 to 10, for example, acarbon number of 1 to 6, or a carbon number of 1 to 3. Examples includemethylene, dimethylene, trimethylene, tetramethylene, andmethyltrimethylene.

In the specification, an alkylene part of the “alkylenedioxy” is thesame as the “alkylene”.

In the specification, the “alkenylene” includes a straight or brancheddivalent carbon chain of a carbon number of 2 to 10, for example, acarbon number of 2 to 6, or a carbon number of 2 to 4, having a doublebond at any available position. Examples include vinylene, propenylene,butenylene, butadienylene, methylpropenylene, pentenylene andhexenylene.

In the specification, the “alkynylene” includes a straight or brancheddivalent carbon chain of a carbon number of 2 to 10, for example, acarbon number of 2 to 6, or a carbon number of 2 to 4, having a triplebond at any available position and, further, optionally having a doublebond. Examples include ethynylene, propynylene, butynylene, pentynyleneand hexynylene.

Examples of the substituent of the “substituted or unsubstitutedalkylene”, the “substituted or unsubstituted alkenylene” and the“substituted or unsubstituted alkynylene” include a group(s) selectedfrom the substituent group α. Examples include halogen and hydroxy.

When “R^(3a) and R^(4a) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle” in the formula (I),

wherein each symbol is as defined above the item (1),includes

These ring may be substituted at any available position with one or moresubstituents selected from the substituent group α, unsubstituted alkyland alkyl substituted with one or more substituents selected from thesubstituent group α.

When “R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle” or “R^(4a) and R^(4b) togetherwith the carbon atom to which they are attached may form a substitutedor unsubstituted carbocycle or a substituted or unsubstitutedheterocycle”,

These ring may be substituted at any available position with one or moresubstituents selected from the substituent group α, unsubstituted alkyland alkyl substituted with one or more substituents selected from thesubstituent group α.

In the specification, the term “solvate” includes, for example, solvateswith organic solvents and hydrates. It can be prepared in accordancewith the known methods. Examples of solvate include a solvate withacetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuranor diethylether. For example, it includes a non-toxic and water-solublehydrate or solvate such as a solvate with ethanol. In the case that ahydrate or solvate is formed, the compound or salt may be coordinatedwith any number of solvate molecules or water molecules.

The compound of formulae (I) and (Ia) to (Ij) includes apharmaceutically acceptable salt. Examples include salts with alkalimetals such as lithium, sodium or potassium; alkaline earth metals suchas calcium; magnesium; transition metals such as zinc or iron; ammonium;organic bases; and amino acids; or salts with inorganic acids such ashydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid,phosphoric acid or hydroiodic acid; and organic acids such as aceticacid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid,oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid,malic acid, benzoic acid, phthalic acid, benzenesulfonic acid,p-toluenesulfonic acid, methanesulfonic acid or ethane sulfonic acid.Particularly, hydrochloric acid, phosphoric acid, tartaric acid ormethanesulfonic acid is preferable. These salts can be formed byordinary methods.

In addition, the compound of formula (I) is not limited to a specificisomer, but includes all possible isomers, such as keto-enol isomers,imine-enamine isomers, diastereoisomers, optical isomers and rotationisomers; and racemate. For example, the compound of formula (I) in whichR^(2a) is hydrogen includes the following tautomers.

Compounds of formulas (Ia) to (Ij) include the similar tautomers.

The compound of formula (I) has an asymmetric carbon atom and includesany optical isomers described below.

Preferable is

In addition, one or more hydrogen, carbon or other atoms of the compoundof formula (I) and (Ia) to (Ij) can be replaced by an isotope of thehydrogen, carbon or other atoms. Compounds of formula (I) include allradiolabeled forms of compounds of formula (I). The “radiolabeled,”“radiolabeled form” and the like of the compound of formula (I) areencompassed by the present invention and useful as a research and/ordiagnostic tool in metabolism pharmacokinetic studies and in bindingassays. It is also useful for a medicament.

Examples of isotopes that can be incorporated into the compound offormula (I) and (Ia) to (Ij) of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,iodine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, ¹²³I and ³⁶Cl, respectively. Radiolabeled compounds ofthe invention can be prepared by methods known in the art. For example,tritiated compounds of formula (I) and (Ia) to (Ij) can be prepared byintroducing tritium into the particular compound of formula (I) and (Ia)to (Ij), for example, by catalytic dehalogenation with tritium. Thismethod may include reacting a suitably halogen-substituted precursor ofa compound of formula (I) and (Ia) to (Ij) with tritium gas in thepresence of a suitable catalyst such as Pd/C, in the presence or absenceof a base. Other suitable methods for preparing tritiated compounds canbe found in the document, “The Preparation and Characterization ofTritiated Neurochemicals,” Chapter 6, pp. 155-192 in Isotopes in thePhysical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A)(1987). ¹⁴C-labeled compounds can be prepared by employing startingmaterials having a ¹⁴C carbon.

(General Preparation)

The compounds of the present invention of formulae (I) and (Ia) to (Ij)can be prepared the method shown below. In the following all steps, whena substituent which interferes with the reaction, e.g. hydroxy,mercapto, amino, formyl, carbonyl, carboxy, is possessed, thesubstituent is protected by the method such as those described inProtective Groups in organic Synthesis, and Theodora W Greene (JohnWiley & Sons) in advance, and the protective group may be removed at adesirable step.

A. Preparation of a Compound of Formula (Ia)

The compound of formula (Ia) can be prepared, for example, according toa method of synthesis shown below.

Synthesis of Compound (Ia)

wherein Hal is halogen and the other symbols are as defined above.

First Step

Compound b can be prepared by adding 3-mercapto propane amidederivative, 3-hydroxy propane amide derivative or 3-amino propane amidederivative, which is commercially available or prepared by the knownmethods, to Compound a, preferably in the presence of an acid such asp-toluene sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuricacid and trifluoroacetic acid, or an amine such as pyrrolidine,piperidine, piperazine and morpholine, and reacting at 0° C. to 150° C.,preferably 0° C. to solvent reflux temperature, for 0.5 to 48 hours,preferably 1 to 24 hours in a solvent such as toluene, dichloromethane,tetrahydrofuran, or a mixed solvent thereof.

Second Step

Compound c can be prepared by adding a halogenating agent such asphosphorus oxychloride, thionyl chloride and oxalyl chloride to Compoundb, and reacting at 0° C. to 100° C., preferably 10° C. to 50° C. for 0.5to 72 hours, preferably 0.5 to 6 hours in a solvent such as dioxane,dichloromethane, tetrahydrofuran, toluene and acetone, or a mixedsolvent thereof.

Third Step

Compound (Ia) can be prepared by adding a primary amine derivative orsecondary amine derivative, which is commercially available or preparedby the known methods, to Compound c, and reacting at 0° C. to 150° C.,preferably 0° C. to solvent reflux temperature, for 0.5 to 48 hours,preferably 1 to 24 hours in a solvent such as dioxane, dichloromethane,tetrahydrofuran, toluene and acetone, or a mixed solvent thereof.

Compound wherein —X— is —S— which is obtained by the above method can beconverted to a compound wherein —X— is —SO— or —SO₂— by oxidizing usingthe known oxidizing agent such as m-chloro perbenzoic acid, hydrogenperoxide and potassium permanganate.

B. Preparation of a Compound of Formula (Ib)

The compound of formula (Ib) can be prepared, for example, according toa method of synthesis shown below.

Synthesis of Compound (Ib)

wherein each symbol is as defined above.

First Step

Compound d can be prepared by adding 2-mercaptobenzamide derivative,2-hydroxybenzamide derivative, 2-aminobenzamide derivative or2-mercaptopyridine amide derivative, which is commercially available orprepared by the known methods, to Compound a, preferably in the presenceof an acid such as p-toluene sulfonic acid, hydrochloric acid,hydrobromic acid, sulfuric acid and trifluoroacetic acid, or an aminesuch as pyrrolidine, piperidine, piperazine and morpholine, and reactingat 0° C. to 150° C., preferably room temperature to solvent refluxtemperature, for 0 to 48 hours, preferably 1 to 24 hours in a solventsuch as toluene, dichloromethane, and tetrahydrofuran, or a mixedsolvent thereof.

Second Step

Compound e can be prepared by adding a halogenating agent such asphosphorus oxychloride, thionyl chloride and oxalyl chloride to Compoundd, and reacting at 0° C. to 100° C., preferably 10° C. to 50° C., for0.5 to 72 hours, preferably 0.5 to 18 hours in a solvent such asdioxane, dichloromethane, tetrahydrofuran, toluene and acetone, or amixed solvent thereof.

Third Step

Compound (Ib) can be prepared by adding primary amine derivative orsecondary amine derivative, which is commercially available or preparedby the known methods, to Compound e, and reacting at 0° C. to 150° C.,preferably 0° C. to solvent reflux temperature, for 0.5 to 48 hours,preferably 1 to 24 hours in a solvent such as dioxane, dichloromethane,tetrahydrofuran, toluene and acetone, or a mixed solvent thereof.

D. Synthesis of Compound (Ic)

wherein Hal is halogen, Pg is an amino protective group, e.g. atert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group andthe other symbols are as defined above.

First Step

Compound g can be prepared by adding compound for its derivative, whichis commercially available or prepared by the known methods, to Compounda, preferably in the presence of an acid such as p-toluene sulfonicacid, hydrochloric acid, hydrobromic acid, sulfuric acid andtrifluoroacetic acid, or an amine such as pyrrolidine, piperidine,piperazine and morpholine, and reacting at 0° C. to 150° C., preferably0° C. to solvent reflux temperature, for 0.5 to 48 hours, preferably 1to 24 hours in a solvent such as toluene, dichloromethane andtetrahydrofuran, or a mixed solvent thereof.

Second Step

Compound h can be prepared by adding a halogenating agent such asphosphorus oxychloride, thionyl chloride and oxalyl chloride to Compoundg, and reacting at 0° C. to 100° C., preferably 10° C. to 50° C., for0.5 to 72 hours, preferably 0.5 to 18 hours in a solvent such asdioxane, dichloromethane, tetrahydrofuran, toluene and acetone, or amixed solvent thereof.

Third Step

Compound i can be prepared by adding an amine having a protective groupPg (shown as PgNH₂), which is commercially available or is prepared bythe known methods, to Compound h, in the presence of a base, e.g.calcium carbonate, palladium catalyst e.g. palladium chloride (PdCl₂) orphosphine ligand, e.g. triphenylphosphine (PPh₃), reacting at 0° C. to150° C., preferably 0° C. to solvent reflux temperature, for 0.5 to 48hours, preferably 1 to 24 hours in a solvent such as dioxane,dichloromethane, tetrahydrofuran, toluene and acetone, or a mixedsolvent thereof.

Fourth Step

Compound (Ic) can be prepared by deprotecting a Pg-group of Compound i.

Deprotections are performed by the method such as those described inProtective Groups in Organic Synthesis, Theodora W Green (John Wiley &Sons). For example, if a protective group is a benzyl group or ap-methoxybenzyl group, deprotection can be performed by catalyticreduction in the presence of hydrogen.

E. D. Synthesis of Compound (Id)

wherein each symbol is as defined above.

Compound (Id) can be prepared by adding amine (shown as R^(2a)R^(2b)NH),which is commercially available or prepared by the known methods, toCompound h, preferably in the presence of a base, e.g. calciumcarbonate, palladium catalyst such as palladium chloride (PdCl₂) orphosphine ligand, e.g. triphenylphosphine (PPh₃), and reacting at 0° C.to 150° C., preferably 0° C. to solvent reflux temperature, for 0.5 to48 hours, preferably 1 to 24 hours in a solvent such as dioxane,dichloromethane, tetrahydrofuran, toluene and acetone, or a mixedsolvent thereof.

F. Synthesis of Compound (If)

wherein each symbol is as defined above.

Compound (If) can be prepared by reacting a reacting agent such as acidchloride, acid anhydride, chlorocarbonic ester and isocyanate, each ofwhich have substituent corresponding to that of the objective compound,e.g. benzoyl chloride, 2-furoylchloride, acetic anhydride,chlorocarbonic benzyl, 2-carbonic-di-tert-butyl or phenyl isocyanate,with Compound (Ie) having substituted or unsubstituted amino in the ringA, in the absence or presence of a base such as pyridine andtriethylamine at −80° C. to 100° C., preferably −20° C. to 40° C., for0.1 to 24 hours, preferably 1 to 12 hours in the absence or presence ofa solvent such as tetrahydrofuran and dichloromethane.

Compound (If) can also be prepared by reacting carboxylic acid whichhave a substituent corresponding to that of the objective compound, e.g.benzoic acid, 2-pyridinecarboxylic acid, with the above Compound (Ie),in the presence of a dehydration condensation agent such asdicyclohexylcarbodiimide, carbonyldiimidazole anddicyclohexylcarbo-di-imide-N-hydroxy benzotriazole at −80° C. to 100°C., preferably −20° C. to 40° C., for 0.1 to 24 hours, preferably 1 to12 hours in a solvent such as dimethylformamide, tetrahydrofuran anddichloromethane.

G. Synthesis of Compound (Ih)

Compound (Ih) can be prepared by the following method A or method B

wherein each symbol is as defined above.

Method A: Condensation Under Acidic Condition

Compound (Ih) can be prepared by adding an acid such as hydrogenchloride, sulfuric acid, trifluoroacetic acid, methanesulfonic acid,trifluoromethanesulfonic acid, and perchloric acid to aryl halide orheteroaryl halide, which is commercially available or prepared by theknown methods (Tetrahedron, 2009, Vol. 65, 757-764) and compound (Ie),and reacting at 0° C. to solvent reflux temperature, preferably 20° C.to 140° C., for 0.1 to 120 hours, preferably 0.5 to 72 hours in asolvent such as methanol, ethanol, isopropyl alcohol, butanol,isobutanol, sec-butanol, acetic acid and water, or a mixed solventthereof.

Method B: Condensation Under Basic Condition

Compound (Ih) can be prepared by reacting aryl halide or heteroarylhalide, which is commercially available or prepared by the known methods(Tetrahedron, 2009, Vol. 65, 757-764), and compound (Ie), in thepresence of a base such as triethylamine, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide,n-butyllithium, lithium hexamethyldisilazide, sodiumhexamethyldisilazide and potassium hexamethyldisilazide, at 0° C. tosolvent reflux temperature, preferably 20° C. to 140° C., for 0.5 to 100hours, preferably 0.5 to 72 hours in a solvent such as toluene,tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, 1,4-dioxane andmethanol.

The reaction can be performed in the presence oftris(dibenzylideneacetone)dipalladium, palladium acetate or palladium(0) prepared in situ or the like and a phosphine ligand such astriphenylphosphine, tri tert-butylphosphine, dicyclohexylbiphenylphosphine, 9,9-dimethyl-4,5-(diphenylphosphino)xanthene(Xantphos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(X-Phos), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl(Ruphos). In the above method, the compounds of the formula (Ih) can beprepared by the reaction at 0° C. to 150° C., preferably 10° C. to 100°C. for 0.5 hour to 72 hours, preferably 1 hour to 24 hours with orwithout microwave irradiation.

H. Synthesis of Compound (Ij)

wherein each symbol is as defined above.

Compound (Ij) can be prepared by reacting Compound (Ii) which have acarboxy group in ring A, with primary amine or secondary amine whichhave a substituent corresponding to that of the objective compound, e.g.aniline, 2-aminopyridine and dimethylamine, in the presence of adehydration condensation agent such as dicyclohexylcarbodiimide,carbonyldiimidazole and dicyclohexylcarbo-di-imide-N-hydroxybenzotriazole, at −80° C. to 100° C., preferably −20° C. to 40° C., for0.1 to 24 hours, preferably 1 to 12 hours in a solvent such asdimethylformamide, tetrahydrofuran and dichloromethane.

In the all above steps, an order of steps to be implemented may beappropriately changed, and each intermediate may be isolated, and usedin a next step.

I. Conversion of Substituent

The synthesis of a compound (Ia) to (Ij) and a compound of which thering A is substituted with various substituent, e.g. substituent of ringB—Z—, can be prepared by the above method or the known methods, e.g. themethod such as those described in Patent Literatures 2 to 4.

Moreover, the optically active isomer of the compound (Ia) to (Ij) canbe prepared by performing an asymmetric synthesis in the suitable stepto prepare an optically active intermediate using a reagent forasymmetric synthesis, or optical resolution of the racemate of theintermediate or the objective compound in the appropriate step. Themethod of optical resolution include the separation of optical isomerusing an optically active column, the kinetics optical resolution usingenzyme reaction or the like, the crystallization and separation ofdiastereomer by the salt formation using chiral acid or chiral base, thepreferential crystallization or the like.

Specific embodiments of the present invention are illustrated below.Each symbol is as defined above.

In the formula (I), the followings are exemplified.

—X— includes —O—, —S—, —SO—, —SO₂— or —N(R^(x))—.

Examples of —X— include —O— or —S—.

R^(x) includes hydrogen, halogen, hydroxy, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

Examples of R^(x) include hydrogen, halogen, hydroxy, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyloxy, substituted or unsubstitutedalkynyloxy, substituted or unsubstituted acyl, substituted orunsubstituted acyloxy, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted amino, substituted or unsubstituted carbamoyl, substitutedor unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

Ring A includes a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle.

Examples of ring A include a substituted or unsubstituted carbocycle.

Examples of ring A include substituted or unsubstituted benzene.

Examples of ring A include the following formula;

Ring A′ and ring B are each independently a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle.

Examples of ring A′ include substituted or unsubstituted benzene.

Examples of ring B include substituted or unsubstituted pyridine,substituted or unsubstituted pyrimidine or substituted or unsubstitutedpyrazine.

—Z— includes -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or -L¹-N(R⁸)-L²-.

Examples of —Z— include -L¹-C(═O)N(R⁸)-L²- wherein L¹ and L² are bond.

L¹ and L² include each independently a bond, substituted orunsubstituted alkylene, substituted or unsubstituted alkenylene orsubstituted or unsubstituted alkynylene, R⁸ includes hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl or substituted orunsubstituted acyl.

—Y— includes substituted or unsubstituted alkenylene, substituted orunsubstituted alkynylene, —(CR⁵R⁶)_(n), —(CR⁵R⁶)_(n)O(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)S(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)SO₂(CR⁵R⁶)_(m),—(CR⁵R⁶)_(n)SO(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)N(R⁷)(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)N(R⁷)(CR⁵R⁶)_(m)—, or—(CR⁵R⁶)_(n)N(R⁷)C(═O)(CR⁵R⁶)_(m)—.

Examples of —Y— include substituted or unsubstituted alkenylene,substituted or unsubstituted alkynylene, or —(CR⁵R⁶)_(n)—.

Examples of —Y— include —(CR⁵R⁶)_(n)—.

Examples of —Y— include —(CR⁵R⁶)_(n)— wherein n is 0.

R⁵ and R⁶ include each independently hydrogen, halogen, hydroxy, nitro,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted carbamoyloxy, substituted orunsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl,substituted or unsubstituted aminosulfinyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

Examples of R⁵ and R⁶ include each independently hydrogen, halogen,hydroxy, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, carboxy, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted carbamoyloxy, substituted orunsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl,substituted or unsubstituted aminosulfinyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclyloxycarbonyl, substituted orunsubstituted carbocyclylthio, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedcarbocyclyloxycarbonyl, substituted or unsubstituted heterocyclylthio,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl.

Examples of R⁵ and R⁶ include each independently hydrogen, halogen,hydroxy, nitro, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted acyl, substituted or unsubstituted acyloxy,cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substitutedor unsubstituted amino, substituted or unsubstituted carbamoyl,substituted or unsubstituted thiocarbamoyl, substituted or unsubstitutedsulfamoyl, a substituted or unsubstituted carbocyclic group, substitutedor unsubstituted carbocyclyloxycarbonyl, a substituted or unsubstitutedheterocyclic group, or substituted or unsubstitutedcarbocyclyloxycarbonyl.

Examples of R⁵ and R⁶ include each independently hydrogen, halogen,hydroxy, nitro, unsubstituted alkyl, unsubstituted alkenyl,unsubstituted alkoxy, unsubstituted alkylthio, unsubstituted acyl,cyano, carboxy, unsubstituted alkoxycarbonyl, unsubstituted amino,unsubstituted carbamoyl, an unsubstituted carbocyclic group,unsubstituted carbocyclyloxycarbonyl, an unsubstituted heterocyclicgroup or unsubstituted carbocyclyloxycarbonyl.

Examples of R⁵ and R⁶ include each independently hydrogen orunsubstituted alkyl.

R⁷ includes hydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl orsubstituted or unsubstituted acyl.

Examples of R⁷ include hydrogen or substituted or unsubstituted alkyl.

n and m include each independently an integer of 0 to 3.

Examples of n and m include 0 simultaneously.

R¹ includes substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted acyl, cyano, carboxy, substituted or unsubstitutedalkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl,substituted or unsubstituted alkynyloxycarbonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, asubstituted or unsubstituted carbocyclic group or a substituted orunsubstituted heterocyclic group.

Examples of R¹ include unsubstituted alkyl of a carbon number of 1 to 3.

R^(2a) and R^(2b) include each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl.

Examples of R^(2a) and R^(2a) are both hydrogen.

R^(3a), R^(3b), R^(4a) and R^(4b) include each independently

hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl.

Examples of R^(3a), R^(3b), R^(4a) and R^(4b) include each independently

hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl.

Examples of R^(3a), R^(3b), R^(4a) and R^(4b) are all hydrogen.

R^(3a) and R^(3b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle.

R^(4a) and R^(4b) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle.

R^(3a) and R^(4a) together with the carbon atom to which they areattached may form a substituted or unsubstituted carbocycle or asubstituted or unsubstituted heterocycle.

For example, R^(3a) and R^(4a) together with the carbon atom to whichthey are attached form a substituted or unsubstituted benzene ring.

Dashed line means the presence or absence of a bond.

When dashed line means the presence of a bond, then R^(3b) and R^(4b)are absent.

When —X— is —O— or —N(R^(x))—, and R^(3a) and R^(4a) together with thecarbon atom to which they are attached form a substituted orunsubstituted benzene ring, then ring A is not (i) phenyl substitutedonly with halogen or (ii) phenyl substituted with substituted orunsubstituted phenyl at m-position.

Specific embodiments of the present invention are the compound offormula:

wherein R^(3a′), R^(3b′), R^(4a′) and R^(4b′) are each independentlyhydrogen, halogen, hydroxy, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl,substituted or unsubstituted sulfamoyl, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substitutedor unsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclyloxycarbonyl,substituted or unsubstituted heterocyclylsulfinyl or substituted orunsubstituted heterocyclylsulfonyl,

R is a substituent selected from the substituent group α, alkylsubstituted with the substituent group α, unsubstituted alkyl, alkenylsubstituted with the substituent group α, unsubstituted alkenyl, alkynylsubstituted with the substituent group α or unsubstituted alkynyl,

s is an integer of 0 to 3, andother symbols are as defined above,its salt, or a solvate thereof.

Specific embodiments are the compound of the above formula (I′) or (I″)wherein

—X— is —O— or —S—,

R¹ is unsubstituted alkyl,R^(2a) and R^(2b) are hydroxy,R^(3a′), R^(3b′), R^(4a′) and R^(4b′) are each independently hydrogen,halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy,alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl, acyloxy, cyano,nitro, carboxy, alkoxycarbonyl, amino, carbamoyl or thiocarbamoyl,sulfamoyl,Ring A′ is substituted or unsubstituted benzene, herein, the substituentis preferably halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy,alkenyloxy, alkynyloxy, acyl, carboxy, alkoxycarbonyl, amino or cyano,ring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazine,herein, the substituent is preferably halogen, hydroxy, alkyl, alkenyl,alkynyl, alkoxy, alkenyloxy, alkynyloxy, acyl, carboxy, alkoxycarbonyl,amino or cyano,L¹ and L² are a bond,R⁸ is hydrogen, alkyl or acyl,R is halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, acyl, carboxy,alkoxycarbonyl, amino, cyano, a carbocyclic group or a heterocyclicgroup,herein the carbocyclic group and the heterocyclic group may besubstituted with one or more substituents selected form a groupconsisting halogen, hydroxy, alkyl and alkoxy, ands is an integer of 0 to 2,its salt, or a solvate thereof.

In another aspect, specific embodiments are the compound of formula (I)wherein

wherein Me is methyl.

The compound of formula (I) wherein Y is a bond. Hereinafter referred toas “Y is y1”.

The compound of formula (I) wherein Y is —CH₂—. Hereinafter referred toas “Y is y2”.

The compound of formula (I) wherein ring A is

The compound of formula (I) wherein ring B is

wherein R^(b1) and R^(b2) are each independently hydrogen, chloro,fluoro, methoxy, butynyloxy, cyano, amino, or carbamoyl.

The compound of formula (I) wherein the combination of Ring B, R^(b1)and R^(b2) (B, R^(b1), R^(b2)) is as follows:

(B1, hydrogen, hydrogen) Hereinafter referred to as “Ring B is b1”.(B1, hydrogen, chloro) Hereinafter referred to as “Ring B is b2”.(B1, hydrogen, fluoro) Hereinafter referred to as “Ring B is b3”.(B1, hydrogen, methoxy) Hereinafter referred to as “Ring B is b4”.(B1, hydrogen, butynyloxy) Hereinafter referred to as “Ring B is b5”.(B1, hydrogen, cyano) Hereinafter referred to as “Ring B is b6”.(B1, hydrogen, amino) Hereinafter referred to as “Ring B is b7”.(B1, hydrogen, carbamoyl) Hereinafter referred to as “Ring B is b8”.(B1, chloro, hydrogen) Hereinafter referred to as “Ring B is b9”.(B1, chloro, chloro) Hereinafter referred to as “Ring B is b10”.(B1, chloro, fluoro) Hereinafter referred to as “Ring B is b11”.(B1, chloro, methoxy) Hereinafter referred to as “Ring B is b12”.(B1, chloro, butynyloxy) Hereinafter referred to as “Ring B is b13”.(B1, chloro, cyano) Hereinafter referred to as “Ring B is b14”.(B1, chloro, amino) Hereinafter referred to as “Ring B is b15”.(B1, chloro, carbamoyl) Hereinafter referred to as “Ring B is b16”.(B1, fluoro, hydrogen) Hereinafter referred to as “Ring B is b17”.(B1, fluoro, chloro) Hereinafter referred to as “Ring B is b18”.(B1, fluoro, fluoro) Hereinafter referred to as “Ring B is b19”.(B1, fluoro, methoxy) Hereinafter referred to as “Ring B is b20”.(B1, fluoro, butynyloxy) Hereinafter referred to as “Ring B is b21”.(B1, fluoro, cyano) Hereinafter referred to as “Ring B is b22”.(B1, fluoro, amino) Hereinafter referred to as “Ring B is b23”.(B1, fluoro, carbamoyl) Hereinafter referred to as “Ring B is b24”.(B1, methoxy, hydrogen) Hereinafter referred to as “Ring B is b25”.(B1, methoxy, chloro) Hereinafter referred to as “Ring B is b26”.(B1, methoxy, fluoro) Hereinafter referred to as “Ring B is b27”.(B1, methoxy, methoxy) Hereinafter referred to as “Ring B is b28”.(B1, methoxy, butynyloxy) Hereinafter referred to as “Ring B is b29”.(B1, methoxy, cyano) Hereinafter referred to as “Ring B is b30”.(B1, methoxy, amino) Hereinafter referred to as “Ring B is b31”.(B1, methoxy, carbamoyl) Hereinafter referred to as “Ring B is b32”.(B1, butynyloxy, hydrogen) Hereinafter referred to as “Ring B is b33”.(B1, butynyloxy, chloro) Hereinafter referred to as “Ring B is b34”.(B1, butynyloxy, fluoro) Hereinafter referred to as “Ring B is b35”.(B1, butynyloxy, methoxy) Hereinafter referred to as “Ring B is b36”.(B1, butynyloxy, cyano) Hereinafter referred to as “Ring B is b37”.(B1, butynyloxy, amino) Hereinafter referred to as “Ring B is b38”.(B1, butynyloxy, carbamoyl) Hereinafter referred to as “Ring B is b39”.(B1, cyano, hydrogen) Hereinafter referred to as “Ring B is b40”.(B1, cyano, chloro) Hereinafter referred to as “Ring B is b41”.(B1, cyano, fluoro) Hereinafter referred to as “Ring B is b42”.(B1, cyano, methoxy) Hereinafter referred to as “Ring B is b43”.(B1, cyano, butynyloxy) Hereinafter referred to as “Ring B is b44”.(B1, cyano, cyano) Hereinafter referred to as “Ring B is b45”.(B1, cyano, amino) Hereinafter referred to as “Ring B is b46”.(B1, cyano, carbamoyl) Hereinafter referred to as “Ring B is b47”.(B1, amino, hydrogen) Hereinafter referred to as “Ring B is b48”.(B1, amino, chloro) Hereinafter referred to as “Ring B is b49”.(B1, amino, fluoro) Hereinafter referred to as “Ring B is b50”.(B1, amino, methoxy) Hereinafter referred to as “Ring B is b51”.(B1, amino, butynyloxy) Hereinafter referred to as “Ring B is b52”.(B1, amino, cyano) Hereinafter referred to as “Ring B is b53”.(B1, carbamoyl, hydrogen) Hereinafter referred to as “Ring B is b54”.(B1, carbamoyl, chloro) Hereinafter referred to as “Ring B is b55”.(B1, carbamoyl, fluoro) Hereinafter referred to as “Ring B is b56”.(B1, carbamoyl, methoxy) Hereinafter referred to as “Ring B is b57”.(B1, carbamoyl, butynyloxy) Hereinafter referred to as “Ring B is b58”.(B1, carbamoyl, cyano) Hereinafter referred to as “Ring B is b59”.(B3, hydrogen, hydrogen) Hereinafter referred to as “Ring B is b60”.(B3, hydrogen, chloro) Hereinafter referred to as “Ring B is b61”.(B3, hydrogen, fluoro) Hereinafter referred to as “Ring B is b62”.(B3, hydrogen, methoxy) Hereinafter referred to as “Ring B is b63”.(B3, hydrogen, butynyloxy) Hereinafter referred to as “Ring B is b64”.(B3, hydrogen, cyano) Hereinafter referred to as “Ring B is b65”.(B3, hydrogen, amino) Hereinafter referred to as “Ring B is b66”.(B3, hydrogen, carbamoyl) Hereinafter referred to as “Ring B is b67”.(B3, chloro, hydrogen) Hereinafter referred to as “Ring B is b68”.(B3, chloro, chloro) Hereinafter referred to as “Ring B is b69”.(B3, chloro, fluoro) Hereinafter referred to as “Ring B is b70”.(B3, chloro, methoxy) Hereinafter referred to as “Ring B is b71”.(B3, chloro, butynyloxy) Hereinafter referred to as “Ring B is b72”.(B3, chloro, cyano) Hereinafter referred to as “Ring B is b73”.(B3, chloro, amino) Hereinafter referred to as “Ring B is b74”.(B3, chloro, carbamoyl) Hereinafter referred to as “Ring B is b75”.(B3, fluoro, hydrogen) Hereinafter referred to as “Ring B is b76”.(B3, fluoro, chloro) Hereinafter referred to as “Ring B is b77”.(B3, fluoro, fluoro) Hereinafter referred to as “Ring B is b78”.(B3, fluoro, methoxy) Hereinafter referred to as “Ring B is b79”.(B3, fluoro, butynyloxy) Hereinafter referred to as “Ring B is b80”.(B3, fluoro, cyano) Hereinafter referred to as “Ring B is b81”.(B3, fluoro, amino) Hereinafter referred to as “Ring B is b82”.(B3, fluoro, carbamoyl) Hereinafter referred to as “Ring B is b83”.(B3, methoxy, hydrogen) Hereinafter referred to as “Ring B is b84”.(B3, methoxy, chloro) Hereinafter referred to as “Ring B is b85”.(B3, methoxy, fluoro) Hereinafter referred to as “Ring B is b86”.(B3, methoxy, methoxy) Hereinafter referred to as “Ring B is b87”.(B3, methoxy, butynyloxy) Hereinafter referred to as “Ring B is b88”.(B3, methoxy, cyano) Hereinafter referred to as “Ring B is b89”.(B3, methoxy, amino) Hereinafter referred to as “Ring B is b90”.(B3, methoxy, carbamoyl) Hereinafter referred to as “Ring B is b91”.(B3, butynyloxy, hydrogen) Hereinafter referred to as “Ring B is b92”.(B3, butynyloxy, chloro) Hereinafter referred to as “Ring B is b93”.(B3, butynyloxy, fluoro) Hereinafter referred to as “Ring B is b94”.(B3, butynyloxy, methoxy) Hereinafter referred to as “Ring B is b95”.(B3, butynyloxy, cyano) Hereinafter referred to as “Ring B is b96”.(B3, butynyloxy, amino) Hereinafter referred to as “Ring B is b97”.(B3, butynyloxy, carbamoyl) Hereinafter referred to as “Ring B is b98”.(B3, cyano, hydrogen) Hereinafter referred to as “Ring B is b99”.(B3, cyano, chloro) Hereinafter referred to as “Ring B is b100”.(B3, cyano, fluoro) Hereinafter referred to as “Ring B is b101”.(B3, cyano, methoxy) Hereinafter referred to as “Ring B is b102”.(B3, cyano, butynyloxy) Hereinafter referred to as “Ring B is b103”.(B3, cyano, cyano) Hereinafter referred to as “Ring B is b104”.(B3, cyano, amino) Hereinafter referred to as “Ring B is b105”.(B3, cyano, carbamoyl) Hereinafter referred to as “Ring B is b106”.(B3, amino, hydrogen) Hereinafter referred to as “Ring B is b107”.(B3, amino, chloro) Hereinafter referred to as “Ring B is b108”.(B3, amino, fluoro) Hereinafter referred to as “Ring B is b109”.(B3, amino, methoxy) Hereinafter referred to as “Ring B is b110”.(B3, amino, butynyloxy) Hereinafter referred to as “Ring B is b111”.(B3, amino, cyano) Hereinafter referred to as “Ring B is b112”.(B3, carbamoyl, hydrogen) Hereinafter referred to as “Ring B is b113”.(B3, carbamoyl, chloro) Hereinafter referred to as “Ring B is b114”.(B3, carbamoyl, fluoro) Hereinafter referred to as “Ring B is b115”.(B3, carbamoyl, methoxy) Hereinafter referred to as “Ring B is b116”.(B3, carbamoyl, butynyloxy) Hereinafter referred to as “Ring B is b117”.(B3, carbamoyl, cyano) Hereinafter referred to as “Ring B is b118”.

The compound of formula (I) wherein the combination of Ring B andR^(1b), (B, R^(1b)) is as follows:

(B2, hydrogen) Hereinafter referred to as “Ring B is b119”.(B2, chloro) Hereinafter referred to as “Ring B is b120”.(B2, fluoro) Hereinafter referred to as “Ring B is b121”.(B2, methoxy) Hereinafter referred to as “Ring B is b122”.(B2, butynyloxy) Hereinafter referred to as “Ring B is b123”.(B2, cyano) Hereinafter referred to as “Ring B is b124”.(B2, amino) Hereinafter referred to as “Ring B is b125”.(B2, carbamoyl) Hereinafter referred to as “Ring B is b126”.(B4, hydrogen) Hereinafter referred to as “Ring B is b127”.(B4, chloro) Hereinafter referred to as “Ring B is b128”.(B4, fluoro) Hereinafter referred to as “Ring B is b129”.(B4, methoxy) Hereinafter referred to as “Ring B is b130”.(B4, butynyloxy) Hereinafter referred to as “Ring B is b131”.(B4, cyano) Hereinafter referred to as “Ring B is b132”.(B4, amino) Hereinafter referred to as “Ring B is b133”.(B4, carbamoyl) Hereinafter referred to as “Ring B is b134”.

The compound of formula (I) wherein the combination of

Y, Ring A and Ring B (r, y, A, b) is as follows:(r1,y1,A1,b1),(r1,y1,A1,b2),(r1,y1,A1,b3),(r1,y1,A1,b4),(r1,y1,A1,b5),(r1,y1,A1,b6),(r1,y1,A1,b7),(r1,y1,A1,b8),(r1,y1,A1,b9),(r1,y1,A1,b10),(r1,y1,A1,b11),(r1,y1,A1,b12),(r1,y1,A1,b13),(r1,y1,A1,b14),(r1,y1,A1,b15),(r1,y1,A1,b16),(r1,y1,A1,b17),(r1,y1,A1,b18),(r1,y1,A1,b19),(r1,y1,A1,b20),(r1,y1,A1,b21),(r1,y1,A1,b22),(r1,y1,A1,b23),(r1,y1,A1,b24),(r1,y1,A1,b25),(r1,y1,A1,b26),(r1,y1,A1,b27),(r1,y1,A1,b28),(r1,y1,A1,b29),(r1,y1,A1,b30),(r1,y1,A1,b31),(r1,y1,A1,b32),(r1,y1,A1,b33),(r1,y1,A1,b34),(r1,y1,A1,b35),(r1,y1,A1,b36),(r1,y1,A1,b37),(r1,y1,A1,b38),(r1,y1,A1,b39),(r1,y1,A1,b40),(r1,y1,A1,b41),(r1,y1,A1,b42),(r1,y1,A1,b43),(r1,y1,A1,b44),(r1,y1,A1,b45),(r1,y1,A1,b46),(r1,y1,A1,b47),(r1,y1,A1,b48),(r1,y1,A1,b49),(r1,y1,A1,b50),(r1,y1,A1,b51),(r1,y1,A1,b52),(r1,y1,A1,b3),(r1,y1,A 1,b54),(r1,y1,A1,b55),(r1,y1,A1,b56),(r1,y1,A1,b57),(r1,y1,A 1,b58),(r1,y1,A 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9),(r5,y2,A3,b120),(r5,y2,A3,b121),(r5,y2,A3,b122),(r5,y2,A3,b123),(r5,y2,A3,b124),(r5,y2,A3,b125),(r5,y2,A3,b126),(r5,y2,A3,b127),(r5,y2,A3,b128),(r5,y2,A3,b129),(r5,y2,A3,b130),(r5,y2,A3,b131),(r5,y2,A3,b132),(r5,y2,A3,b133),(r5,y2,A3,b134),(r5,y2,A4,b1),(r5,y2,A4,b2),(r5,y2,A4,b3),(r5,y2,A4,b4),(r5,y2,A4,b5),(r5,y2,A4,b6),(r5,y2,A4,b7),(r5,y2,A4,b8),(r5,y2,A4,b9),(r5,y2,A4,b10),(r5,y2,A4,b11),(r5,y2,A4,b12),(r5,y2,A4,b13),(r5,y2,A4,b14),(r5,y2,A4,b15),(r5,y2,A4,b16),(r5,y2,A4,b17),(r5,y2,A4,b18),(r5,y2,A4,b19),(r5,y2,A4,b20),(r5,y2,A4,b21),(r5,y2,A4,b22),(r5,y2,A4,b23),(r5,y2,A4,b24),(r5,y2,A4,b25),(r5,y2,A4,b26),(r5,y2,A4,b27),(r5,y2,A4,b28),(r5,y2,A4,b29),(r5,y2,A4,b30),(r5,y2,A4,b31),(r5,y2,A4,b32),(r5,y2,A4,b33),(r5,y2,A4,b34),(r5,y2,A4,b35),(r5,y2,A4,b36),(r5,y2,A4,b37),(r5,y2,A4,b38),(r5,y2,A4,b39),(r5,y2,A4,b40),(r5,y2,A4,b41),(r5,y2,A4,b42),(r5,y2,A4,b43),(r5,y2,A4,b44),(r5,y2,A4,b45),(r5,y2,A4,b46),(r5,y2,A4,b47),(r5,y2,A4,b48),(r5,y2,A4,b49),(r5,y2,A4,b50),(r5,y2,A4,b51),(r5,y2,A4,b52),(r5,y2,A4,b53),(r5,y2,A4,b54),(r5,y2,A4,b55),(r5,y2,A4,b56),(r5,y2,A4,b57),(r5,y2,A4,b58),(r5,y2,A4,b59),(r5,y2,A4,b60),(r5,y2,A4,b61),(r5,y2,A4,b62),(r5,y2,A4,b63),(r5,y2,A4,b64),(r5,y2,A4,b65),(r5,y2,A4,b66),(r5,y2,A4,b67),(r5,y2,A4,b68),(r5,y2,A4,b69),(r5,y2,A4,b70),(r5,y2,A4,b71),(r5,y2,A4,b72),(r5,y2,A4,b73),(r5,y2,A4,b74),(r5,y2,A4,b75),(r5,y2,A4,b76),(r5,y2,A4,b77),(r5,y2,A4,b78),(r5,y2,A4,b79),(r5,y2,A4,b80),(r5,y2,A4,b81),(r5,y2,A4,b82),(r5,y2,A4,b83),(r5,y2,A4,b84),(r5,y2,A4,b85),(r5,y2,A4,b86),(r5,y2,A4,b87),(r5,y2,A4,b88),(r5,y2,A4,b89),(r5,y2,A4,b90),(r5,y2,A4,b91),(r5,y2,A4,b92),(r5,y2,A4,b93),(r5,y2,A4,b94),(r5,y2,A4,b95),(r5,y2,A4,b96),(r5,y2,A4,b97),(r5,y2,A4,b98),(r5,y2,A4,b99),(r5,y2,A4,b100),(r5,y2,A4,b101),(r5,y2,A4,b102),(r5,y2,A4,b103),(r5,y2,A4,b104),(r5,y2,A4,b105),(r5,y2,A4,b106),(r5,y2,A4,b107),(r5,y2,A4,b108),(r5,y2,A4,b109),(r5,y2,A4,b110),(r5,y2,A4,b111),(r5,y2,A4,b112),(r5,y2,A4,b113),(r5,y2,A4,b114),(r5,y2,A4,b115),(r5,y2,A4,b116),(r5,y2,A4,b117),(r5,y2,A4,b118),(r5,y2,A4,b119),(r5,y2,A4,b120),(r5,y2,A4,b121),(r5,y2,A4,b122),(r5,y2,A4,b123),(r5,y2,A4,b124),(r5,y2,A4,b125),(r5,y2,A4,b126),(r5,y2,A4,b127),(r5,y2,A4,b128),(r5,y2,A4,b129),(r5,y2,A4,b130),(r5,y2,A4,b131),(r5,y2,A4,b132),(r5,y2,A4,b133) or(r5,y2,A4,b134).

The present compounds are useful in disease induced by the production,secretion or deposition of amyloid β protein, and are effective intreatment and/or prevention, and symptom improvement of such as dementiaof the Alzheimer's type (Alzheimer's disease, senile dementia ofAlzheimer type), Down's syndrome, memory impairment, prion disease(Creutzfeldt-Jakob disease), mild cognitive impairment (MCI), Dutch typeof hereditary cerebral hemorrhage with amyloidosis, cerebral amyloidangiopathy, other type of degenerative dementia, mixed dementia withAlzheimer's and vascular type, dementia with Parkinson's Disease,dementia with progressive supranuclear palsy, dementia withCortico-basal degeneration, Alzheimer's disease with diffuse Lewy bodydisease, age-related macular degeneration, Parkinson's Disease, amyloidangiopathy and so on.

Example of “treating Alzheimer's disease” includes prevention ofaggravation of mild cognitive impairment (MCI) and prevention of onsetof familial Alzheimer's disease. Example of “a pharmaceuticalcomposition for treating Alzheimer's disease” includes pharmaceuticalcomposition for prevention of aggravation of mild cognitive impairment(MCI) and prevention of onset of familial Alzheimer's disease.

Since the present compound has high inhibitory activity on BACE1, and/orhas high selectivity on other enzymes, it can be a medicament withreduced side effect. Further, since the compound has high effect ofreducing amyloid β production in a cell system, particularly, has higheffect of reducing amyloid β production in brain, it can be an excellentmedicament. In addition, by converting the compound into an opticallyactive compound having suitable stereochemistry, the compound can be amedicament having a larger safety margin on the side effect. Inaddition, the present compound also has advantages that metabolismstability is high, solubility is high, oral absorbability is high, goodbioavailability is exhibited, clearance is good, brain transference ishigh, a half life is high, non-protein binding rate is high, hERGchannel inhibition is low, CYP inhibition is low, CYP MBI (irreversibleinhibition (mechanism-based inhibition)) is low and/or an Ames test isnegative.

The present compounds can be administrated in combination with otherpharmaceutical agents such as other therapeutic or preventive drugs forAlzheimer's disease, e.g., acetylcholinesterase and the like. Thepresent compounds can be treated with concomitantly with theanti-dementia agents such as Donepezil Hydrochloride, Tacrine,Galantamine, Rivastigmine, Zanapezil, Memantine, and Vinpocetine.

When the present compound is administered to a human, it can beadministered orally as powders, granules, tablets, capsules, pills,solutions, or the like, or parenterally as injectables, suppositories,transdermal absorbable agents, inhalations, or the like. In addition,the present compound can be formulated into pharmaceutical preparationsby adding pharmaceutical additives such as excipients, binders, wettingagents, disintegrating agents, lubricants and the like, which aresuitable for formulations and an effective amount of the presentcompound.

A dose is different depending on state of disease, an administrationroute, and an age and a weight of a patient, and is usually 0.1 μg to 1g/day, preferably 0.01 to 200 mg/day when orally administered to anadult, and is usually 0.1 μg to 10 g/day, preferably 0.1 to 2 g/day whenparenterally administered.

EXAMPLES

Following examples and test examples illustrate the present invention inmore detail, but the present invention is not limited by these examples.

¹H-NMR was measured in deuterium chloroform (CDCl₃) usingtetramethylsilane as an internal standard, or measured indimethylsulfoxide-D6 (DMSO-d₆). δ values were shown as ppm. Bindingconstants (J) were shown as Hz. In the data, s, d, t, sext, m, br or brsmeans singlet, doublet, triplet, sextet, multiplet, broad or broadsinglet, respectively.

In example, the meaning of each abbreviation is as follows:

Me methylBz benzoylBoc tert-butoxycarbonylMPM p-methoxybenzylTHF tetrahydrofuran

LC/MS data of the present compound were measured under any of thefollowing condition, and a retention time and [M+H]⁺ are shown.

(Method A)

Column: Xbridge (registered trade name) C18 (5 μm, i.d. 4.6×50 mm)(Waters)Flow rate: 3 mL/min.UV detection wavelength: 254 nmMobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing acetonitrile solutionGradient: performing linear gradient of 10% to 100% solvent [B] for 3minutes, and keeping 100% solvent [B] for 1 minute

(Method B)

column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)Flow rate: 1.6 mL/min.UV detection wavelength: 254 nmMobile phase: [A] 0.1% formic acid-containing aqueous solution; [B] 0.1%formic acid-containing acetonitrile solutionGradient: performing linear gradient of 10% to 100% solvent [B] for 3minutes, and keeping 100% solvent [B] for 1 minute

Example 1

First Step

To a solution of compound 1 (15.00 mg) in ethanol (300 ml) was added 10%Palladium-carbon (3.00 g), and the mixture was reacted under hydrogenatmosphere at room temperature for 8 hours. After removing the insolublematerial by filtration, the filtrate was concentrated to give compound 2(18.75 g) as a crude product.

¹H-NMR (CDCl₃) δ:2.61 (3H, d, J=4.9 Hz), 6.80 (1H, ddd, J=8.8, 4.0, 3.1Hz), 6.93 (1H, dd, J=10.6, 8.8 Hz), 7.12 (1H, dd, J=5.9, 3.1 Hz).

Second Step

To a solution of compound 2 (12.56 g) obtained at First step inN,N-dimethylformamide (130 ml) were added potassium carbonate (45.30 g)and 4-methoxy benzyl bromide (52.80 g), and the mixture was reacted at50° C. for 7 hours and 30 minutes. After water was added to the mixture,the mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated invacuo. The obtained residue was purified by silica gel columnchromatography to give compound 3 (24.90 g).

¹H-NMR (CDCl₃) δ: 2.58 (3H, d, J=5.0 Hz), 3.78 (6H, s), 4.52 (4H, s),6.78-6.94 (6H, m), 7.11 (4H, d, J=8.5 Hz), 7.20-7.25 (1H, m).

Third Step

To a solution of compound 3 (24.90 g) in toluene (249 ml) were addedp-toluene sulfonic acid (22.49 g) and 3-mercapto propane amide (7.99 g).It was heated under reflux for 14 hours being removed generated water.After water was added to the mixture, the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The obtained residue was purified by silica gel columnchromatography to give compound 4 (1.49 g).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.13-2.21 (2H, m), 2.39-2.48 (2H, m),3.79 (6H, s), 4.49-4.63 (4H, m), 6.19 (1H, s), 6.60-6.67 (2H, m),6.83-6.90 (5H, m), 7.14 (4H, d, J=8.7 Hz).

Fourth Step

To compound 4 (2.48 g) was added phosphorus oxychloride (12.4 ml). Itwas stirred at room temperature for 23 hours. The phosphorus oxychloridewas evaporated in vacuo to give the compound 5 as a crude product.

Fifth Step

To a solution of compound 5 obtained at the Fourth step in toluene (12.9ml) was added 2-4-dimethoxy benzylamine (17.26 g) at room temperature,and the mixture was heated at 100° C. for 5 hours and 30 minutes. Waterwas added thereto and the mixture was extracted with ethyl acetate anddried over anhydrous sodium sulfate. The solvent was evaporated invacuo. The obtained residue was purified by silica gel columnchromatography to give compound (I-13) (1.82 g).

¹H-NMR (CDCl₃) δ: 1.95 (3H, d, J=2.0 Hz), 2.00-2.11 (2H, m), 2.31-2.35(2H, m), 3.78-3.81 (14H, m), 4.22-4.52 (5H, m), 6.41-6.49 (4H, m),6.79-6.83 (5H, m), 7.05 (4H, d, J=8.7 Hz), 7.19-7.26 (1H, m).

Sixth Step

To a solution of compound (I-13) was added trifluoroacetic acid (18.2ml) It was heated under reflux for 22 hours. After water and potassiumcarbonate were added to the mixture, the mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate.The solvent was evaporated in vacuo. The obtained residue was purifiedby silica gel column chromatography to give compound (I-14) (0.63 g).

2.45 (2H, m), 2.57 (1H, ddd, J=13.8, 9.1, 4.8 Hz), 2.70 (1H, ddd,J=13.8, 5.7, 4.8 Hz), 3.50 (2H, s), 6.50 (1H, dt, J=8.5, 3.3 Hz), 6.58(1H, dd, J=7.0, 3.3 Hz), 6.82 (1H, dd, J=11.8, 8.5 Hz).

Seventh Step

5-methylpyrazine-2-carbonic acid (0.11 g) was dissolved in methanol (1ml) and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl-4-methylmorpholiniumchloride (0.26 g) were added thereto. The mixture was stirred at roomtemperature for 5 minutes, a solution of compound (I-14) (0.15 g) inmethanol (1.5 ml) was added thereto.

After being stirred at room temperature for 1 hour, ice water and sodiumhydroxide solution were added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo. The obtained residue waspurified by silica gel column chromatography to give compound (I-1)(0.23 g).

¹H-NMR (CDCl₃) δ: 1.97 (3H, d, J=1.7 Hz), 2.32-2.49 (2H, m), 2.58 (1H,ddd, J=13.8, 8.4, 5.5 Hz), 2.71-2.75 (4H, m), 4.44 (2H, s), 7.06 (1H,dd, J=11.4, 8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.76 (1H, ddd, J=8.7,3.9, 2.7 Hz), 8.42 (1H, d, J=0.9 Hz), 9.35 (1H, d, J=0.9 Hz), 9.57 (1H,s).

Example 2

First Step

To a solution of compound 6 (2.00 g) in toluene (30 ml) were addedpyrrolidine (0.04 g) and 5-chloro 2-hydroxybenzamide (0.87 g). It washeated under reflux for 18 hours being removed generated water. Afterwater were added to the mixture, the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate. Thesolvent was evaporated in vacuo. The obtained residue was purified bysilica gel column chromatography to give compound 7 (0.72 g).

¹H-NMR (CDCl₃) δ: 1.93 (3H, s), 3.81 (6H, s), 4.36 (2H, d, J=16.8 Hz),4.49 (2H, d, J=16.8 Hz), 6.52-6.61 (4H, m), 6.78-6.87 (5H, m), 6.95 (4H,d, J=8.1 Hz), 7.11 (1H, dd, J=8.7, 2.6 Hz), 7.74 (1H, d, J=2.6 Hz).

Second Step

To compound 7 (0.48 g) was added phosphorus oxychloride (1.5 ml). It wasstirred at 80° C. for 2.5 hours. The phosphorus oxychloride wasevaporated in vacuo to give the compound 8 as a crude product.

Third Step

To a solution of compound 8 obtained in Second step in toluene (5 ml)was added 2-4-dimethoxybenzylamine (1.47 g) with stirring at roomtemperature. It was heated under reflux for 1.5 hours. After water wasadded to the mixture, the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated in vacuo. The obtained residue was purified by silica gelcolumn chromatography to give compound (I-15) (0.1 g).

¹H-NMR (CDCl₃) δ: 1.97 (3H, s), 3.78-3.80 (12H, m), 4.35-4.45 (6H, m),6.40-6.45 (4H, m), 6.73-6.88 (7H, m), 7.01-7.13 (6H, m).

Fourth Step

To compound (I-15) (0.1 g) was added trifluoroacetic acid (1.5 ml), themixture was heated under reflux for 8 hours. Water and potassiumcarbonate were added to the mixture and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo. The obtained residue waspurified by silica gel column chromatography to give compound (I-16)(0.01 g).

¹H-NMR (CDCl₃) δ: 1.94 (3H, s), 6.43-6.51 (1H, m), 6.73-6.79 (2H, m),6.89 (1H, d, J=8.7 Hz), 7.21-7.31 (2H, m).

Example 3

First Step

To a solution of compound 6 (39.61 g) in toluene (594 ml) were addedp-toluene sulfonic acid (1.91 g) and 2-mercaptobenzamide (18.51 g). Itwas heated under reflux for 15 hours being removed generated water.After water was added to the mixture, the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The obtained residue was purified by silica gel columnchromatography to give compound 9 (2.9 g).

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 3.80 (6H, s), 4.36 (4H, s), 6.45-6.48(2H, m), 6.78-6.80 (5H, m), 6.90-7.05 (6H, m), 7.10-7.30 (2H, m), 7.92(1H, dd, J=7.9, 1.5 Hz).

Second Step

To compound 9 (0.31 g) was added phosphorus oxychloride (3.1 ml). It wasstirred at 80° C. for 15 hours. The phosphorus oxychloride wasevaporated in vacuo. After the evaporation, the obtained residue waspoured into ice water, and the mixture was extracted with ethyl acetateand dried over anhydrous sodium sulfate. The solvent was evaporated invacuo to give compound 10 as a crude product.

Third Step

To a solution of compound 10 obtained in Second step in toluene (1.6 ml)was added 2-4-dimethoxybenzylamine (0.49 g) at room temperature. It washeated under reflux for 2.5 hours. Water was added to the mixture andthe mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate. The solvent was evaporated invacuo. The obtained residue was purified by silica gel columnchromatography to give compound (I-17) (0.27 g).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 3.72-3.78 (12H, m), 4.33-4.38 (6H, m),6.38-6.48 (4H, m), 6.78-6.82 (5H, m), 7.01-7.41 (10H, m).

Fourth Step

To compound (I-17) (0.27 g) was added trifluoroacetic acid (1.4 ml), themixture was heated under reflux for 3 hours. Water and potassiumcarbonate were added to the mixture, and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated in vacuo. The obtained residue waspurified by silica gel column chromatography to give compound (I-18)(0.04 g).

¹H-NMR (CDCl₃) δ: 1.91 (3H, d, J=1.2 Hz), 6.47 (1H, ddd, J=8.5, 3.7, 3.1Hz), 6.81 (1H, dd, J=11.7, 8.5 Hz), 6.98 (1H, dd, J=6.8, 3.0 Hz),7.11-7.17 (1H, m), 7.28-7.30 (2H, m), 7.55-7.57 (1H, m).

The following compounds are prepared in accordance with the aboveexamples. In the tables, RT means a retention time (minutes).

TABLE 1-1 NMR Comp. (solvent, shift value: MS LC/MS LC/MS No. Structureascending order) [M + 1] RT Method I-1

1H-NMR (CDCl3) δ: 1.97 (3H, d, J = 1.7 Hz), 2.32-2.49 (2H, m), 2.58 (1H,ddd, J = 13.8, 8.4, 5.5 Hz), 2.71-2.75 (4H, m), 4.44 (2H, s), 7.06 (1H,dd, J = 11.4, 8.7 Hz), 7.49 (1H, dd, J = 8.7, 2.7 Hz), 7.76 (1H, ddd, J= 8.7, 3.9, 2.7 Hz), 8.42 (1H, d, J = 0.9 Hz), 9.35 (1H, d, J = 0.9 Hz),9.57 (1H, s). I-2

413 1.06 A I-3

418 1.31 B I-4

402 1.32 B

TABLE 1-2 NMR Comp. (solvent, shift value: MS LC/MS LC/MS No. Structureascending order) [M + 1] RT Method I-5

¹H-NMR (CDCl₃) δ: 1.94 (3H, s), 6.43-6.51 (1H, m), 6.73-6.79 (2H, m),6.89 (1H, d, J = 8.7 Hz), 7.21-7.31 (2H, m). 436 1.24 A I-6

370 1.09 A I-7

408 1.25 B I-8

424 1.36 B I-9

417 1.14 B

TABLE 1-3 NMR Comp. (solvent, shift value: MS LC/MS LC/MS No. Structureascending order) [M + 1] RT Method I-10

417 1.13 B I-11

1H-NMR (CDCl3) δ: 1.97 (3H, s), 4.86 (2H, bs), 6.96- 7.25 (4H, m), 7.69(1H, dd, J = 6.6, 2.7 Hz), 7.80-7.83 (1H, m), 8.18 (1H, dd, J = 8.1, 2.1Hz), 8.40 (1H, dd, J = 8.1, 0.6 Hz), 8.87 (1H, J = 1.2 Hz), 9.75 (1H,bs). 421 1.2 A I-12

1H-NMR (CDCl3) δ: 1.99 (3H, d, J = 0.9 Hz), 6.63 (1H, dt, J = 2.7, 8.7Hz), 6.73 (1H, dd, J = 9.9, 2.7 Hz), 7.07 (1H, dd, J = 11.1, 9.0 Hz),7.30 (1H, dd, J = 6.9, 2.7 Hz), 7.71 (1H, dd, J = 6.9, 2.7 Hz),7.80-7.86 (1H, m), 8.19 (1H, dd, J = 8.1, 2.1 Hz), 8.41 (1H, d, J = 7.2Hz), 8.88 (1H, s), 9.77 (1H, bs). 421 1.25 A

TABLE 1-4 NMR Comp. (solvent, shift value: MS LC/MS LC/MS No. Structureascending order) [M + 1] RT Method I-13

¹H-NMR (CDCl₃) δ: 1.95 (3H, d, J = 2.0 Hz), 2.00-2.11 (2H, m), 2.31-2.35(2H, m), 3.78-3.81 (14H, m), 4.22-4.52 (5H, m), 6.41-6.49 (4H, m), 6.79-6.83 (5H, m), 7.05 (4H, d, J = 8.7 Hz), 7.19- 7.26 (1H, m). I-14

1H-NMR (CDCl₃) δ: 1.92 (3H, d, J = 1.7 Hz), 2.26-2.45 (2H, m), 2.57 (1H,ddd, J = 13.8, 9.1, 4.8 Hz), 2.70 (1H, ddd, J = 13.8, 5.7, 4.8 Hz), 3.50(2H, s), 6.50 (1H, dt, J = 8.5, 3.3 Hz), 6.58 (1H, dd, J = 7.0, 3.3 Hz),6.82 (1H, dd, J = 11.8, 8.5 Hz). I-15

¹H-NMR (CDCl₃) δ: 1.97 (3H, s), 3.78-3.80 (12H, m), 4.35-4.45 (6H, m),6.40-6.45 (4H, m), 6.73-6.88 (7H, m), 7.01-7.13 (6H, m). I-16

¹H-NMR (CDCl₃) δ: 1.94 (3H, s), 6.43-6.51 (1H, m), 6.73-6.79 (2H, m),6.89 (1H, d, J = 8.7 Hz), 7.21-7.31 (2H, m).

TABLE 1-5 NMR Comp. (solvent, shift value: MS LC/MS LC/MS No. Structureascending order) [M + 1] RT Method I-17

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 3.72-3.78 (12H, m), 4.33-4.38 (6H, m),6.38-6.48 (4H, m), 6.78-6.82 (5H, m), 7.01-7.41 (10H, m). I-18

¹H-NMR (CDCl₃) δ: 1.91 (3H, d, J = 1.2 Hz), 6.47 (1H, ddd, J = 8.5, 3.7,3.1 Hz), 6.81 (1H, dd, J = 11.7, 8.5 Hz), 6.98 (1H, dd, J = 6.8, 3.0Hz), 7.11-7.17 (1H, m), 7.28-7.30 (2H, m), 7.55-7.57 (1H, m). I-19

392 0.7 A

The effect of the present compound is confirmed by the following testExamples.

Test Example 1 Assay of BACE1 Inhibiting Activity

48.5 μL of substrate peptide solution (Biotin-XSEVNLDAEFRHDSGC-Eu:X=ε-amino-n-capronic acid, Eu=Europium cryptate) was added to each wellof 96-hole half-area plate (a black plate: Costar), and after additionof 0.5 μl of the test compound (dissolved in N,N′-dimethylformaldehyde)and 1 μl of Recombinant human BACE1 (R&D Systems), the reaction mixturewas incubated at 30° C. for 3 hours. The substrate peptide wassynthesized by reacting Cryptate TBPCOOH mono SMP (CIS biointernational) with Biotin-XSEVNLDAEFRHDSGC (Peptide Institute, Inc.).The final concentrations of the substrate peptide and Recombinant humanBACE1 were adjusted to 18 nmol/L and 7.4 nmol/L, respectively, and thereaction was performed in sodium acetate buffer (50 mmol/L sodiumacetate, pH 5.0, 0.008% Triton X-100). After the incubation forreaction, 50 μl of 8.0 μg/ml Streptavidin-XL665 (CIS bio international)dissolved in phosphate buffer (150 mmol/L K₂HPO₄—KH₂PO₄, pH 7.0, 0.008%Triton X-100, 0.8 mol/L KF) was added to each well and left stand at 30°C. for an hour. After then, fluorescence intensity was measured(excitation wavelength: 320 nm, measuring wavelength: 620 nm and 665 nm)using Wallac 1420 multilabel counter (Perkin Elmer life sciences).Enzymatic activity was determined from counting ratio of each wavelength(10,000×Count 665/Count 620) and 50% inhibitory concentration (IC₅₀)against the enzymatic activity was calculated.

(Result)

TABLE 2 Comp. Test example 1 No. IC50(μM) I-2 0.010 I-8 0.066 I-12 0.061

Compounds I-1, 3 to 7 and 9 to 11 showed the IC₅₀ value of 1 μM or less.

Test Example 2 Measurement of β-Amyloid (Aβ) Production InhibitoryEffect in Cell

Neuroblastoma SH-SY5Y cells (SH/APPwt) with human wild-type β-APPexcessively expressed therein were prepared at 8×10⁵ cells/mL, and 150μl portions thereof were inoculated into each well of a 96-well cultureplate (Falcon). The cells were cultured for 2 hours at 37° C. in a 5%gaseous carbon dioxide incubator. Then, a solution which had beenpreliminarily prepared by adding and suspending the test compound (DMSO(dimethyl sulfoxide) solution) so as to be 2 μl/50 μl medium was addedto the cell sap. Namely, the final DMSO concentration was 1%, and theamount of the cell culture was 200 μl. After the incubation wasperformed for 24 hours from the addition of the test compound, 100 μl ofthe culture supernatant was collected from each fraction. The amount ofthe Aβ in each fraction was measured.

The Aβ amount was measured as follows. 10 μl of a homogeneous timeresolved fluorescence (HTRF) measurement reagent (Amyloid β 1-40peptide; IBA Molecular Holding, S.A.) and 10 μl of the culturesupernatant were put into a 384-well half area microplate (blackmicroplate, Costar) and mixed with each other, and then left standingovernight at 4° C. while the light was shielded. Then, the fluorescenceintensity (excitation wavelength: 337 nm, measurement wavelength: 620 nmand 665 nm) was measured with a Wallac 1420 multilabel counter (PerkinElmer life sciences). The Aβ amount was determined from the count rateat each measurement wavelength (10000×Count 665/Count 620), and theamount needed to inhibit Aβ production by 50% (IC₅₀) was calculated fromat least six different dosages. Table 3 shows the IC₅₀ value of eachtest compound.

(Result)

TABLE 3 Comp. Test example 2 No. IC50(μM) I-2 <0.001  I-8 0.019 I-120.015

Compounds I-1, 3 to 7, 9 to 11 and 19 showed the IC₅₀ value of 1 μM orless.

Test Example 3 Lowering Effect on Brain β Amyloid in Rats

A test compound was suspended in 0.5% methylcellulose, the finalconcentration was adjusted to 2 mg/mL, and this was orally administeredto male Crj:SD rat (7 to 9 weeks old) at mg/kg. In a vehicle controlgroup, only 0.5% methylcellulose was administered, and an administrationtest was performed at 3 to 8 animals per group. A brain was isolated 3hours after administration, a cerebral hemisphere was isolated, a weightthereof was measured, the hemisphere was rapidly frozen in liquidnitrogen, and stored at −80° C. until extraction date. The frozencerebral hemisphere was transferred to a homogenizer manufactured byTeflon (registered trade name) under ice cooling, a 5-fold volume of aweight of an extraction buffer (containing 1% CHAPS({3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate}), 20mmol/L Tris-HCl (pH 8.0), 150 mmol/L NaCl, Complete (Roche) proteaseinhibitor) was added, up and down movement was repeated, and this washomogenized to solubilize for 2 minutes. The suspension was transferredto a centrifugation tube, allowed to stand on an ice for 3 hours or moreand, thereafter centrifuged at 100,000×g, 4° C. for 20 minutes. Aftercentrifugation, the supernatant was transferred to an ELISA plate(product No. 294-62501, Wako Junyaku Kogyo) for measuring β amyloid 40.ELISA measurement was performed according to the attached instruction.The lowering effect was calculated as a ratio compared to the brain βamyloid 40 level of vehicle control group of each test.

Test Example 4 CYP3A4 Fluorescent MBI Test

The CYP3A4 fluorescent MBI test is a test of investigating enhancementof CYP3A4 inhibition of a compound by a metabolism reaction, and thetest was performed using, as CYP3A4 enzyme expressed in Escherichia coliand employing, as an index, a reaction in which7-benzyloxytrifluoromethylchmarin (7-BFC) is debenzylated by the CYP3A4enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin (HFC)emitting fluorescent light.

The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC;pre-reaction time, 0 or minutes; reaction time, 15 minutes; reactiontemperature, 25° C. (room temperature); CYP3A4 content (expressed inEscherichia coli), at pre-reaction 62.5 pmol/mL, at reaction 6.25pmol/mL (at 10-fold dilution); test drug concentration, 0.625, 1.25,2.5, 5, 10, 20 μmol/L (six points).

An enzyme in a K-Pi buffer (pH 7.4) and a test drug solution as apre-reaction solution were added to a 96-well plate at the compositionof the pre-reaction, a part of it was transferred to another 96-wellplate so that it was 1/10 diluted by a substrate in a K-Pi buffer, NADPHas a co-factor was added to initiate a reaction as an index (withoutpreincubation) and, after a predetermined time of a reaction,acetonitrile/0.5 mol/L Tris(trishydroxyaminomethane)=4/1 was added tostop the reaction. In addition, NADPH was added to a remainingpreincubation solution to initiate a preincubation (with preincubation)and, after a predetermined time of a preincubation, a part wastransferred to another plate so that it was 1/10 diluted with asubstrate and a K-Pi buffer to initiate a reaction as an index. After apredetermined time of a reaction, acetonitrile/0.5 mol/LTris(trishydroxyaminomethane)=4/1 was added to stop the reaction. Forthe plate on which each index reaction had been performed, a fluorescentvalue of 7-HFC which is a metabolite was measured with a fluorescentplate reader. (Ex=420 nm, Em=535 nm).

Addition of only DMSO which is a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solution,and IC₅₀ was calculated by reverse-presumption by a logistic model usinga concentration and an inhibition rate. When a difference between IC₅₀values is 5 μM or more, this was defined as (+) and, when the differenceis 3 μM or less, this was defined as (−).

(Result) Compound I-4: (−) Test Example 5 CYP Inhibition Test

Using commercially available pooled human hepatic microsome, andemploying, as markers, O-deethylation of 7-ethoxyresorufin (CYP1A2),methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation ofmephenyloin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6) andhydroxylation of terfenadine (CYP3A4) as typical substrate metabolismreactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6,3A4), an inhibitory degree of each metabolite production amount by atest compound was assessed.

The reaction conditions were as follows: substrate, 0.5 μmol/Lethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/LS-mephenitoin (CYP2C19), 5 mol/L dextromethorphan (CYP2D6), 1 μmol/Lterfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature,37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; testdrug concentration, 1, 5, 10, 20 μmol/L (four points).

Each five kinds of substrates, human hepatic microsome, and a test drugin 50 mmol/L Hepes buffer as a reaction solution was added to a 96-wellplate at the composition as described above, NADPH, as a cofactor wasadded to initiate metabolism reactions as markers and, after theincubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v)solution was added to stop the reaction. After the centrifugation at3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in thesupernatant was quantified by a fluorescent multilabel counter andtributamide hydroxide (CYP2CP metabolite), mephenyloin 4′ hydroxide(CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), andterfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reactionsystem was adopted as a control (100%), remaining activity (%) wascalculated at each concentration of a test drug added as the solutionand IC₅₀ was calculated by reverse presumption by a logistic model usinga concentration and an inhibition rate.

(Result)

Compound I-19: five kinds >17 μM

Test Example 8 FAT Test

Each 20 μL of freeze-stored Salmonella typhimurium (TA98 and TA100strain) is inoculated in 10 mL of liquid nutrient medium (2.5% Oxoidnutrient broth No. 2), and the cultures are incubated at 37° C. undershaking for 10 hours. 9 mL of TA98 culture is centrifuged (2000×g, 10minutes) to remove medium, and the bacteria is suspended in 9 mL ofMicro F buffer (K₂HPO₄: 3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SO₄: 1 g/L,trisodium citrate dihydrate: 0.25 g/L, MgSO₄. 7H₂O: 0.1 g/L), and thesuspension is added to 110 mL of Exposure medium (Micro F buffercontaining Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL).3.16 mL of TA100 culture is added to 120 mL of Exposure medium toprepare the test bacterial solution. 588 μL of the test bacterialsolution (or mixed solution of 498 μl of the test bacterial solution and90 μL of the S9 mix in the case with metabolic activation system) aremixed with each 12 μL of the following solution: DMSO solution of thetest substance (eight dose levels from maximum dose 50 mg/mL at 2-foldratio); DMSO as negative control; 50 μg/mL of 4-nitroquinoline-1-oxideDMSO solution as positive control for TA98 without metabolic activationsystem; 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSOsolution as positive control for TA100 without metabolic activationsystem; 40 μg/mL of 2-aminoanthracene DMSO solution as positive controlfor TA98 with metabolic activation system; or 20 μg/mL of2-aminoanthracene DMSO solution as positive control for TA100 withmetabolic activation system. 12 μL of the solution and 588 μL of thetest bacterial solution (a mixed solution of 498 μl of the testbacterial solution and 90 μL of S9 mix with metabolic activationcondition) were mixed and incubated at 37° C. under shaking for 90minutes. 460 μL of the bacterial solution exposed to the test substanceis mixed with 2300 μL of Indicator medium (Micro F buffer containingbiotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo CresolPurple: 37.5 μg/mL), each 50 μL is dispensed into 48 wells per dose inthe microwell plates, and is subjected to stationary cultivation at 37°C. for 3 days. A well containing the bacteria, which has obtained theability of proliferation by mutation in the gene coding amino acid(histidine) synthetase, turns the color from purple to yellow due to pHchange. The number of the yellow wells among the 48 total wells per doseis counted and evaluated in comparing that of the negative controlgroup. (−) means that mutagenicity is negative and (+) means thatmutagenicity is positive.

Test Example 7(1) Solubility Test

A 2-fold dilution series (12 points) of a 10 mM solution of a testcompound in DMSO was added to a medium (JP-I, JP-II) (2%), andsolubility was assessed by 3 stages (High; >40 μM, Medium; 3-40 μM, Low;<3 μM) from a turbidity after 4 hours (crystallization information).

(Result) Compound I-9: High Test Example 7(2) Solubility Test

The solubility of each compound is determined under 1% DMSO additionconditions. A 10 mM solution of the compound is prepared with DMSO, and6 μL of the compound solution is added to 594 μL of an artificialintestinal juice (water and 118 mL of 0.2 mol/L NaOH reagent are addedto 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent to reach1000 mL) with a pH of 6.8. The mixture is left standing for 16 hours at25° C., and the mixture is vacuum-filtered. The filtrate is two-folddiluted with methanol/water=1/1, and the compound concentration in thefiltrate is measured with HPLC or LC/MS/MS by the absolute calibrationmethod.

Test Example 8 Metabolism Stability Test

Using a commercially available pooled human hepatic microsomes, a testcompound was reacted for a constant time, a remaining rate wascalculated by comparing a reacted sample and an unreacted sample,thereby, a degree of metabolism in liver was assessed.

A reaction was performed (oxidative reaction) at 37° C. for 0 minute or30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/Lmagnesium chloride) containing 0.5 mg protein/mL of human livermicrosomes. After the reaction, 50 μL of the reaction solution was addedto 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at3000 rpm for 15 minutes. The test compound in the supernatant wasquantified by LC/MS/MS, and a remaining amount of the test compoundafter the reaction was calculated, letting a compound amount at 0 minutereaction time to be 100%.

(Result) Compound I-19: 97% Test Example 9 hERG Test

For the purpose of assessing risk of an electrocardiogram QT intervalprolongation, effects on delayed rectifier K+ current (I_(Kr)), whichplays an important role in the ventricular repolarization process, isstudied using HEK293 cells expressing human ether-a-go-go related gene(hERG) channel.

After a cell is retained at a membrane potential of −80 mV by whole cellpatch clamp method using an automated patch clamp system (PatchXpress7000A, Axon Instruments Inc.), I_(Kr) induced by depolarization pulsestimulation at +40 mV for 2 seconds and, further, repolarization pulsestimulation at −50 mV for 2 seconds was recorded. After the generatedcurrent is stabilized, extracellular solution (NaCl: 135 mmol/L, KCl:5.4 mmol/L, NaH₂PO₄: 0.3 mmol/L, CaCl₂.2H₂O: 1.8 mmol/L, MgCl₂.6H₂O: 1mmol/L, glucose: 10 mmol/L, HEPES (4 (2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test compound hadbeen dissolved at an objective concentration is applied to the cellunder the room temperature condition for 10 minutes. From the recordingI_(Kr), an absolute value of the tail peak current is measured based onthe current value at the resting membrane potential using an analysissoftware (DataXpress ver. 1, Molecular Devices Corporation). Further,the % inhibition relative to the tail peak current before application ofthe test substance is calculated, and compared with the vehicle-appliedgroup (0.1% dimethyl sulfoxide solution) to assess influence of the testsubstance on I_(Kr).

Test Example 9 Powder Solubility Test

Appropriate amounts of the test substances are put into appropriatecontainers. To the respective containers are added 200 μL of JP-1 fluid(sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to reach 1000mL), 200 μL of JP-2 fluid (phosphate buffer (pH 6.8) 500 mL and water500 mL), and 200 μL of 20 mmol/L TCA (sodium taurocholate)/JP-2 fluid(TCA 1.08 g and water to reach 100 mL). In the case that the testcompound is dissolved after the addition of the test fluid, the bulkpowder is added as appropriate. The containers are sealed, and shakenfor 1 hour at 37° C. The mixtures are filtered, and 100 μL of methanolis added to each of the filtrate (100 μL) so that the filtrates aretwo-fold diluted. The dilution ratio may be changed if necessary. Thedilutions are observed for bubbles and precipitates, and then thecontainers are sealed and shaken. Quantification is performed by HPLCwith an absolute calibration method.

Test Example 11 BA Test

Materials and Methods for studies on oral absorption

(1) Animal: Mouse or Rats

(2) Breeding conditions: mouse or rats were allowed to freely take solidfeed and sterilized tap water.(3) Dose and grouping: orally or intravenously administered at apredetermined dose; grouping was as follows (Dose depends on thecompound)Oral administration: 1 to 30 mg/kg (n=2 to 3)Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)(4) Preparation of dosing solution: for oral administration, in asolution or a suspension state; for intravenous administration, in asolubilized state(5) Administration method: in oral administration, forcedly administerinto ventriculus with oral probe; in intravenous administration,administer from caudal vein with a needle-equipped syringe(6) Evaluation items: blood was collected over time, and the plasmaconcentration of drug was measured by LC/MS/MS(7) Statistical analysis: regarding the transition of the plasmaconcentration, the area under the plasma concentration-time curve (AUC)was calculated by non-linear least squares program WinNonlin (Registeredtrade name), and the bioavailability (BA) was calculated from the AUCsof the oral administration group and intravenous administration group

(Result) Compound I-1: 93.4 Test Example 12 Brain Distribution Studies

Intravenous administration is carried out to a rat by 0.5 mg/mL/kgdosage of a text compound. 30 minutes later, all blood is drawn fromvena cava inferior under isoflurane anesthesia for death fromexsanguination. Then, the brain was extracted and 20-25% of homogenatethereof was prepared with distilled water. On the other hand, theobtained blood is used as plasma after centrifuging. Then, to the brainsample was added the control plasma at 1:1. To the plasma samples wasadded the control brains at 1:1. Each sample was measured usingLC/MS/MS. The obtained area ratio (a brain/plasma) was used for thebrain Kp value.

(Result) Compound I-11: 5.8. Formulation Example 1

A granule containing the following ingredients is produced.

Ingredient Compound of formula (I) 10 mg Lactose 700 mg Corn starch 274mg HPC-L 16 mg 1000 mg

The compound of formula (I), and lactose are passed through a 60 meshsieve. Corn starch is passed through a 120 mesh sieve. These are mixedwith a V-type mixer. A HPC-L (low viscosity hydroxypropylcellulose)aqueous solution is added. To the mixed powder is added a HPC-L (lowviscosity hydroxypropylcellulose) aqueous solution, this is kneaded,granulated (extrusion granulation, pore diameter 0.5 to 1 mm), anddried. The resulting dry granule is passed through a vibration sieve(12/60 mesh) to obtain a granule.

Formulation Example 2

A granule for filling a capsule containing the following ingredients isproduced.

Ingredient Compound of formula (I) 15 mg Lactose 90 mg Corn starch 42 mgHPC-L 3 mg 150 mg

The compound of formula (I), and lactose are passed through a 60 meshsieve. Corn starch is passed through a 120 mesh sieve. These are mixed,a HPC-L solution is added to the mixed powder, this is kneaded,granulated, and dried. The resulting dry granule is adjusted in a size,and 150 mg of it is filled into a No. 4 hard gelatin capsule.

Formulation Example 3

A tablet containing the following ingredients is produced.

Ingredient Compound of formula (I) 10 mg Lactose 90 mg Microcrystallinecellulose w30 mg CMC-Na 15 mg Magnesium stearate 5 mg 150 mg

The compound of formula (I), lactose, microcrystalline cellulose, andCMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 meshsieve, and mixed. Magnesium stearate is mixed into the mixed powder toobtain a mixed powder for tabletting. The present mixed powder isdirectly compressed to obtain a 150 mg of a tablet.

Formulation Example 4

The following ingredients are warmed, mixed, and sterilized to obtain aninjectable.

Ingredient Compound of formula (I) 3 mg Nonionic surfactant 15 mgPurified water for injection 1 ml

INDUSTRIAL APPLICABILITY

The present compound can be a medicament useful as an agent for treatinga disease induced by production, secretion and/or deposition of amyloidβ protein.

1. A compound of formula (I):

wherein —X— is —O—, —S—, —SO—, —SO₂— or —N(R^(x))—, R^(x) is hydrogen,halogen, hydroxy, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedacyl, substituted or unsubstituted acyloxy, cyano, carboxy, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, ring A is a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle, —Y— issubstituted or unsubstituted alkenylene, substituted or unsubstitutedalkynylene, —(CR⁵R⁶)_(n)—, —(CR⁵R⁶)_(n)O(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)S(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)SO₂(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)SO(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)(CR⁵R⁶)_(m)—,—(CR⁵R⁶)_(n)N(R⁷)(CR⁵R⁶)_(m)—, —(CR⁵R⁶)_(n)C(═O)N(R⁷)(CR⁵R⁶)_(m)—, or—(CR⁵R⁶)_(n)N(R⁷)C(═O)(CR⁵R⁶)_(m)—, R⁵ and R⁶ are each independently,hydrogen, halogen, hydroxy, nitro, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkenylthio, substituted or unsubstituted alkynylthio, substituted orunsubstituted acyl, substituted or unsubstituted acyloxy, cyano,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted amino, substituted orunsubstituted carbamoyl, substituted or unsubstituted carbamoyloxy,substituted or unsubstituted thiocarbamoyl, substituted or unsubstitutedsulfamoyl, substituted or unsubstituted aminosulfinyl, substituted orunsubstituted alkylsulfinyl, substituted or unsubstitutedalkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedalkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, asubstituted or unsubstituted carbocyclic group, substituted orunsubstituted carbocyclyloxy, substituted or unsubstitutedcarbocyclylthio, substituted or unsubstituted carbocyclylalkyl,substituted or unsubstituted carbocyclylalkoxy, substituted orunsubstituted carbocyclyloxycarbonyl, substituted or unsubstitutedcarbocyclylsulfinyl, substituted or unsubstituted carbocyclylsulfonyl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted heterocyclyloxy, substituted or unsubstitutedheterocyclylthio, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted heterocyclylalkoxy, substituted orunsubstituted heterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, R⁷ is hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl or substituted or unsubstituted acyl, n and m areeach independently an integer of 0 to 3, R¹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted acyl, cyano,carboxy, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkenyloxycarbonyl, substituted or unsubstitutedalkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substitutedor unsubstituted thiocarbamoyl, a substituted or unsubstitutedcarbocyclic group or a substituted or unsubstituted heterocyclic group,R^(2a) and R^(2b) are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted acyl, substituted orunsubstituted alkoxycarbonyl or substituted or unsubstituted carbamoyl,R^(3a), R^(3b), R^(4a) and R^(4b) are each independently hydrogen,halogen, hydroxy, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkenyloxy,substituted or unsubstituted alkynyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkenylthio, substituted orunsubstituted alkynylthio, substituted or unsubstituted acyl,substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substitutedor unsubstituted alkoxycarbonyl, substituted or unsubstitutedalkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl,substituted or unsubstituted amino, substituted or unsubstitutedcarbamoyl, substituted or unsubstituted thiocarbamoyl, substituted orunsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkenylsulfinyl, substituted orunsubstituted alkynylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substitutedor unsubstituted alkynylsulfonyl, a substituted or unsubstitutedcarbocyclic group, substituted or unsubstituted carbocyclyloxy,substituted or unsubstituted carbocyclylthio, substituted orunsubstituted carbocyclylalkyl, substituted or unsubstitutedcarbocyclylalkoxy, substituted or unsubstituted carbocyclyloxycarbonyl,substituted or unsubstituted carbocyclylsulfinyl, substituted orunsubstituted carbocyclylsulfonyl, a substituted or unsubstitutedheterocyclic group, substituted or unsubstituted heterocyclyloxy,substituted or unsubstituted heterocyclylthio, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstitutedheterocyclylalkoxy, substituted or unsubstitutedheterocyclyloxycarbonyl, substituted or unsubstitutedheterocyclylsulfinyl or substituted or unsubstitutedheterocyclylsulfonyl, R^(3a) and R^(3b) together with the carbon atom towhich they are attached may form a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle, R^(4a) andR^(4b) together with the carbon atom to which they are attached may forma substituted or unsubstituted carbocycle or a substituted orunsubstituted heterocycle, R^(3a) and R^(4a) together with the carbonatom to which they are attached may form a substituted or unsubstitutedcarbocycle or a substituted or unsubstituted heterocycle, dashed linemeans the presence or absence of a bond, when dashed line means thepresence of a bond, then R^(3b) and R^(4b) are absent, provided thatwhen —X— is —O— or —N(R^(x))—, and R^(3a) and R^(4a) together with thecarbon atom to which they are attached form a substituted orunsubstituted benzene ring, then ring A is not (i) phenyl substitutedonly with halogen or (ii) phenyl substituted with substituted orunsubstituted phenyl at m-position, its pharmaceutically acceptable saltor a solvate thereof.
 2. The compound according to claim 1 wherein Y is—(CR⁵R⁶)_(n)— and n is 0, its pharmaceutically acceptable salt or asolvate thereof.
 3. The compound according to claim 2 wherein —X— is —O—or —S—, its pharmaceutically acceptable salt or a solvate thereof. 4.The compound according to claim 1 wherein ring A is a group of formula:

wherein ring A′ and ring B are each independently a substituted orunsubstituted carbocycle or a substituted or unsubstituted heterocycle,—Z— is -L¹-C(═O)N(R⁸)-L²-, -L¹-N(R⁸)C(═O)-L²- or -L¹-N(R⁸)-L²-, L¹ andL² are each independently a bond, substituted or unsubstituted alkylene,substituted or unsubstituted alkenylene or substituted or unsubstitutedalkynylene, R⁸ is hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl or substituted or unsubstituted acyl, its pharmaceuticallyacceptable salt or a solvate thereof.
 5. The compound according to claim4 wherein —Z— is —C(═O)N(R⁸)—, its pharmaceutically acceptable salt or asolvate thereof.
 6. The compound according to claim 4 wherein ring A′ issubstituted or unsubstituted benzene, its pharmaceutically acceptablesalt or a solvate thereof.
 7. The compound according to claim 4 whereinring B is substituted or unsubstituted pyridine, substituted orunsubstituted pyrimidine or substituted or unsubstituted pyrazine, itspharmaceutically acceptable salt or a solvate thereof.
 8. The compoundaccording to claim 1 wherein R^(3a), R^(3b), R^(4a) and R^(4b) are allhydrogen, its pharmaceutically acceptable salt or a solvate thereof. 9.The compound according to claim 1 wherein R^(3a) and R^(4a) togetherwith the carbon atom to which they are attached form a substituted orunsubstituted benzene ring, its pharmaceutically acceptable salt or asolvate thereof.
 10. The compound according to claim 1 wherein R¹ is C1to C3 unsubstituted alkyl, its pharmaceutically acceptable salt or asolvate thereof.
 11. The compound according to claim 1 wherein R^(2a)and R^(2b) are both hydrogen, its pharmaceutically acceptable salt or asolvate thereof.
 12. A pharmaceutical composition comprising thecompound according to claim 1, its pharmaceutically acceptable salt or asolvate thereof as an active ingredient.
 13. A pharmaceuticalcomposition having BACE1 inhibitory activity comprising the compoundaccording to claim 1, its pharmaceutically acceptable salt or a solvatethereof as an active ingredient.
 14. The pharmaceutical compositionaccording to claim 12, which is a medicament for treating or preventingthe diseases induced by production, secretion or deposition of amyloid-βproteins.
 15. The pharmaceutical composition according to claim 12,which is a medicament for treating or preventing Alzheimer's disease.16. A method for inhibiting BACE1 activity comprising administering thecompound according to claim 1, its pharmaceutically acceptable salt or asolvate thereof.
 17. The compound according to claim 1, itspharmaceutically acceptable salt or a solvate thereof for use in amethod for inhibiting BACE1 activity.
 18. A method for treating orpreventing diseases induced by production, secretion or deposition ofamyloid-β proteins comprising administering the compound according toclaim 1, its pharmaceutically acceptable salt or a solvate thereof. 19.The compound according to claim 1, its pharmaceutically acceptable saltor a solvate thereof for use in a method for treating or preventingdiseases induced by production, secretion or deposition of amyloid-βproteins.
 20. A method for treating or preventing Alzheimer's diseasecomprising administering the compound according to claim 1, itspharmaceutically acceptable salt or a solvate thereof.
 21. The compoundaccording to claim 1, its pharmaceutically acceptable salt or a solvatethereof for use in a method for treating or preventing Alzheimer'sdisease.